
==== Front
Crit Care
Critical Care
1364-8535
1466-609X
BioMed Central London

39227925
5069
10.1186/s13054-024-05069-w
Review
Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives
Hu Dongxue 1
Sheeja Prabhakaran Harshini 1
Zhang Yuan-Yuan 3
Luo Gaoxing 45
He Weifeng whe761211@hotmail.com

45
Liou Yih-Cherng dbslyc@nus.edu.sg

12
1 https://ror.org/01tgyzw49 grid.4280.e 0000 0001 2180 6431 Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543 Singapore
2 grid.4280.e 0000 0001 2180 6431 Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, 119077 Singapore
3 https://ror.org/011ashp19 grid.13291.38 0000 0001 0807 1581 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041 China
4 grid.410570.7 0000 0004 1760 6682 State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
5 Chongqing Key Laboratory for Disease Proteomics, Chongqing, 400038 China
3 9 2024
3 9 2024
2024
28 29214 5 2024
17 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.

Keywords

Sepsis
Mitochondrial dysfunction
Immune response
Mitochondria-targeted therapy
http://dx.doi.org/10.13039/501100001459 Ministry of Education - Singapore A-8000985 Liou Yih-Cherng issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

To advance understanding of sepsis and septic shock, the task force convened by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine introduced the "Sepsis-3" definition between 2014 and 2015 [1]. This update redefined sepsis as life-threatening organ dysfunction caused by a dysregulated inflammatory response to infection [1]. Sepsis contributes to 11 million deaths out of the 48.9 million reported cases, accounting for 19.7% of all global deaths in 2017 [2, 3]. The request for novel therapeutic targets in sepsis management assumes paramount importance.

Mitochondria are primary energy generators and participate in cellular processes, such as maintaining redox balance, buffering Ca2+, and initiating apoptosis [4]. A mitochondrion contains two membranes, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), forming the matrix and intermembrane space (IMS) [5]. The mitochondrial respiratory chain comprises five complexes localized within the IMM: complex I, II, III, IV, and V. Complexes I–IV receive electrons, creating an electrochemical gradient of proton across the IMM referred to as mitochondrial membrane potential (ΔΨm). This ΔΨm is utilized by the complex V (F1F0 ATP synthase) to drive the production of ATP [6].

Accumulative evidence suggests that mitochondria play crucial roles in the pathogenesis of sepsis [7, 8]. Both laboratory studies and clinical investigations have documented the increase in mitochondrial damage during sepsis [9, 10]. Mitochondrial dysfunction occurs when mitochondria, fail to function properly upon damage. Mitochondria are not only involved in energy production, but also play critical roles in regulating cell metabolism and several cellular processes. The effects of mitochondrial dysfunction are enormous, including energy deficiency and activation of multiple pathways that alter cell function and fate. In the context of sepsis, the damaged mitochondria actively partake in shaping the inflammatory response via various signaling pathways [11]. Advances in mitochondria-targeted therapeutics have demonstrated that improving mitochondrial quality can reduce sepsis-induced inflammation, organ failure, and consequent mortality [12–14]. Thus, regulating mitochondrial quality is emerging as a promising strategy for sepsis treatment.

This review seeks to explore the complex mechanisms underlying mitochondrial dysfunction in sepsis and its profound influence on immune dysregulation. Additionally, we highlight promising interventions targeted at mitochondria that have shown therapeutic effectiveness in preclinical sepsis models. By comprehensively understanding the interplay between mitochondrial integrity and immune responses, we strive to pave the way for the development of novel and effective therapeutic approaches in combating sepsis-associated morbidity and mortality.

Mitochondrial stress and damage during sepsis

Sepsis triggers significant stress to mitochondria within immune cells and various tissues, leading to structural distortions, potential loss, and a marked decrease in respiratory activity. This section explores the specifics of the mitochondrial damage and the underlying mechanisms.

Mitochondrial damage

Despite the limited amount, clinical data clearly indicate mitochondrial dysfunction during sepsis. For instance, Japiassu and colleagues demonstrated that peripheral blood mononuclear cells (PBMCs) from septic shock patients have impaired mitochondrial ATP synthase activity [15]. Garrabou et al. observed inhibition of respiratory complexes in the PBMCs from septic patients without shock or multi-organ failure (MOF), suggesting that mitochondrial impairment precede these symptoms [16]. The platelets from septic patients showed lower activity of mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH), complex I, I/III, and IV [17]. In addition to blood cells, muscle tissue of septic patients has also been reported with mitochondrial dysfunction and ATP depletion [18, 19]. Severe cardiac impairment has been observed in the non-surviving septic patients, with histologic analysis of heart sections showing mitochondrial cristae derangement (Table 1) [20].Table 1 Mitochondrial damage during sepsis

Species	Inducer	Tissue/cell	Time/stage	Mitochondrial assessments	Refs.	
Human	N.A	PBMCs	With shock	Oxygen consumption reduced; ATP synthase activity declined	[15]	
Human	N.A	PBMCs	Early stages without shock or MOF	CI, CIII, and CIV activity decreased; ΔΨm reduced; Oxygen consumption reduced; Circulating free mtDNA in plasma increased	[16]	
Human	N.A	Platelet	Severe sepsis or septic shock	Mitochondrial NADH, CI, CI & III, and CIV, succinate dehydrogenase (SDH) activity decreased	[17]	
Human	N.A	Leg and serratus anterior muscle	With MOF and requiring mechanical ventilation	Leg muscle: CI activity unchanged; CIV activity and ATP reduced; morphology unchanged

Serratus anterior muscle: CI activity decreased; CIV activity, ATP, and morphology unchanged

The observed changes probably because of reduced mitochondrial mass

	[28]	
Human	N.A	Vastus lateralis muscle	With MOF	Structure swollen or damaged; Respiratory protein subunits and transcripts reduced	[19]	
Human	N.A	Heart	Post-mortem	Mitochondrial cristae impaired	[20]	
Mouse	LPS	Heart	24 h	Mitochondrial number and volume reduced; Mitochondrial displayed internal vesicles, disrupted structure, and loss of cristae; expression of OXPHOS genes decreased	[29]	
Mouse	LPS	Kidney	18 h	Mitochondrial swollen and cristae reduced; Cytochrome c oxidase protein level and activity decreased; Mitochondrial gene expression was suppressed	[30]	
Mouse	LPS	Liver	0–48 h	mtDNA levels/integrity, complex I activity, and ATP level reduced; mtROS increased	[31]	
Mouse	LPS	Leg muscle	28 days	Mitochondrial respiration reduced; CV activity was reduced; Mitochondrial fission increased;	[32]	
Mouse	CLP	Brain	24 h	Oxidative phosphorylation uncoupled; ΔΨm dissipated; CIV activity reduced; CI-III activity unchanged	[33]	
Mouse	CLP	Heart	12 h	mtDNA copy number reduced; mitochondrial respiration reduced; ATP level declined; mitochondrial biogenesis marker PGC1β reduced; mitochondrial Ca2+ uptake capacity declined	[34]	
Mouse	CLP	Kidney	6–36 h	ROS increased; CI, CII & CIII activity and ATP decreased; CIV activity unchanged	[35]	
Rat	LPS	Heart	0–24 h	Mitochondria displayed structural abnormalities; CI, II, and IV activities reduced; ATP synthesis decreased	[36]	
Rat	LPS	Liver	2 h	Mitochondrial oxygen consumption reduced despite the total oxygen consumption unchanged; mitochondria became swollen and pale, with indistinct cristae and disrupted membranes; ATP/ADP ratio unchanged	[37]	
Rat	S. pneumoniae	Heart	24 h	ROS increased; mtDNA damaged; mitochondrial membrane disrupted; CI, II-III, IV and V activity reduced	[38]	
Cat	LPS	Liver	4 h	Respiratory activity was impaired; mitochondrial ultrastructural injured (swollen and membrane disruption)	[39]	
Baboon	E. coli	Heart	72 h or after death	CI, and II activities reduced; CIII was less affected	[25]	
MOF multi-organ failure. CI, II, III, IV, V: mitochondrial respiratory complex I, II, III, IV, V. ΔΨm: mitochondrial membrane potential

In animal models, cecal ligation and puncture (CLP), endotoxins/bacteria administration, and colon ascendens stent peritonitis (CASP) are commonly utilized to trigger sepsis [21]. Studies using these models support the clinical findings, highlighting the substantial impact of sepsis on mitochondrial homeostasis (Table 1). However, it is essential to acknowledge the presence of conflicting data showing unchanged or even increased mitochondrial activity in some cases, as previously discussed [22, 23]. Variables such as the nature of the septic insult, the severity of sepsis, timing of assessments, and methods of measurement may contribute to the discrepancies [24–26].

In addition, the common practice of using isolated cells or mitochondria from septic tissues for complex activity assays may not accurately reflect the in vivo mitochondrial status. This issue arises from the absence of circulating substances, such as cytokines, in vitro, which play pivotal roles in regulating mitochondrial respiration [16]. For instance, Boulos et al. demonstrated that serum from septic patients significantly reduced endothelial cell mitochondrial respiration compared to serum from healthy individuals, revealing the impact of circulating substances on mitochondrial function during sepsis [27].

Furthermore, normalization methods profoundly influence the evaluation of mitochondrial function. In a previous study, Fredriksson et al. measured the complex I activities in intercostal muscle mitochondria from septic patients and observed a 60% decrease when normalized to the dry weight of the muscle. However, no difference was found when normalization was conducted against citrate synthase activity. This was because the citrate synthase activity also declined during sepsis [28], emphasizing the importance of meticulous methodological consideration in such analyses.

Mechanisms of mitochondrial damage

Mitochondrial injury during sepsis is regulated by several factors, including reactive nitrogen species (RNS)/reactive oxygen species (ROS), mitophagy, mitochondrial dynamics, and mitochondrial membrane permeabilization, etc. In this section, we will examine the regulatory roles of these factors in mitochondrial health amidst septic conditions.

RNS/ROS burst

One of the well-exploited triggers of mitochondrial damage is nitric oxide (⋅NO), an RNS that is produced by inducible nitric oxide synthase (iNOS) [40]. ⋅NO could be converted to other reactive nitrogen species such as nitrite (NO2−) and nitrogen dioxide (·NO2) (Fig. 1) [41]. Escames et al. have investigated the role of iNOS in skeletal muscle mitochondria using a CLP mouse model. They observed a reduction in mitochondrial respiratory complex activity accompanied by elevated expression of iNOS during sepsis. In contrast, the iNOS-deficient mice did not exhibit such mitochondrial impairment [40]. A similar observation has been observed in the liver mitochondria of LPS-treated mice [42]. In line with these, inhibition of mitochondrial respiration induced by septic serum could be mitigated by the nitric oxide synthase inhibitor [27]. These data collectively suggest that iNOS play a crucial role in mitochondrial damage during sepsis.Fig. 1 Pathways of RNS and ROS production in sepsis. Excessive nitric oxide is generated by both cytosolic and mitochondrial iNOS during sepsis. The nitric oxide can be converted to other reactive nitrogen species (RNS), such as nitrite and nitrogen dioxide. On the other hand, excessive reactive oxygen species (ROS) are produced by NOXs and mitochondrial electron transport chain (ETC). Nitric oxide and superoxide react to form additional derivatives, notably the highly toxic peroxynitrite. The accumulation of these reactive species inflicts damage to cellular components, including lipids, proteins, and nucleic acids, thereby compromising mitochondrial respiration and integrity

Sepsis also stimulates the formation of ROS. Superoxide radical (O2·−) originates from nicotinamide adenine dinucleotide phosphate oxidases (NOXs) and mitochondria ETC [43]. O2·− is considered unstable and can be converted to other types of ROS (Fig. 1) [44]. On the other hand, declines in the antioxidative system happen during sepsis. For example, sirtuin proteins, which can protect cells from oxidative stress, have been found to decrease after septic insults [45, 46]. Oxidative stress occurs when ROS level overwhelms the antioxidant defense system in cells, causing damage to lipids, proteins, and nucleic acids [47].

Mechanistically, ·NO selectively binds to complex IV, where it competes with O2 for the binuclear CuB/cytochrome a3 center, resulting in a reversible inhibition of the complex IV [48]. While ·NO is relatively unreactive, its reaction with ROS gives rise to a series of more reactive derivatives [49]. Peroxynitrite (ONOO–) is one of the highly toxic derivatives (Fig. 1). Peroxynitrite can cause impairments to mitochondria via oxidation, irreversibly inhibiting mitochondrial complex I, CII, CIV, ATP synthase, and several critical enzymes. Consequently, the RNS/ROS exert a profound inhibitory effect on mitochondrial respiration and contribute to mitochondrial damage during sepsis [50].

Mitophagy

Mitophagy is a specialized form of autophagy that selectively degrades damaged mitochondria (Fig. 2a) [51]. Impaired mitophagy prevents mitochondrial turnover, leading to the accumulation of dysfunctional mitochondria [52]. Growing evidence shows that inhibition of mitophagy occurs in immune cells during the inflammatory response. Yu et al. found that Caspase-1 in macrophages cleaves Parkin to inhibit mitophagy upon inflammasome activation [53]. Similarly, Patoli et al. demonstrated mitophagy inhibition in the LPS/IFN-γ-treated macrophage cells, CLP mouse model, and septic patients, revealing caspases 1/11 dependent PINK1 degradation in the early stage of inflammation [54]. Additionally, inflammation-induced pro-IL-1α can interact with cardiolipin, preventing it from serving as a mitophagy receptor [55]. AMP-activated protein kinase (AMPK) is a regulator of autophagy, which positively regulates mitochondrial clearance by activating unc-51 like autophagy activating kinase 1 (ULK1) [56]. TLR4 signaling has been reported to prevent the activation of AMPK in neutrophil and macrophage [57]. Thus, lack of AMPK activation could be another reason for the accumulation of damaged mitochondria in sepsis.Fig. 2 Pathways of mitophagy and mitochondrial dynamics. a The most extensively studied mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon ΔΨm loss, PINK1 is stabilized on the OMM, where it recruits and activates Parkin. Parkin subsequently ubiquitinates mitochondrial surface proteins, signaling the autophagosome to encapsulate the dysfunctional mitochondrion. Adaptor proteins including p62, Optineurin (OPTN), calcium binding and coiled-coil domain-containing protein 2 (NDP52), tax1-binding protein 1 (TAX1BP1), and next to BRCA1 gene 1 protein (NBR1) play a role in linking the ubiquitin chains to microtubule-associated protein 1 light chain 3 (LC3) on phagophores. On the other hand, some mitochondrial receptor proteins (or lipids) such as FUN14 domain containing 1 (FUNDC1), prohibitin (PHB), BCL2 interacting protein3 (BNIP3), Nip3-like protein X (NIX), cardiolipin, and syntaxin 17 (STX17) can recruit phagophore membranes independent of ubiquitin. The autophagosome finally fuses with a lysosome for the degradation and recycling of mitochondria. b Mitochondrial dynamics is regulated by several dynamin-related GTPases, including Mfn1/2, OPA1, Drp1, Fis1, MiD49/51, and Mff. Mfn1/2 facilitate the fusion of the OMM, while OPA1 is responsible for the fusion of the IMM. The fission process is initiated by the endoplasmic reticulum (ER)-mediated pre-constriction of mitochondria. Drp1 is recruited to the pre-constricted sites by receptors (Mff, Fis1, and MiD49/51). After binding to OMM, Drp1 oligomerizes into ring-shaped filaments. Hydrolysis of GTP by Drp1 results in constriction and closure of the ring. Dnm2 is finally recruited to the constricting site to complete the fission. In addition to the ER, lysosome and Golgi-derived vesicles have also been reported to regulate mitochondrial fission

Interestingly, activation of mitophagy also occurs during immune response. Ip and colleagues showed that interleukin 10 (IL-10) promotes mitophagy by inhibiting the mammalian target of rapamycin (mTOR) in macrophages [58]. Moreover, nuclear factor κB (NF-κB) facilitates mitophagy by inducing the expression of autophagic receptor p62. This NF-κB-p62-mitophagy pathway exists as a self-limiting mechanism to prevent excessive inflammation and maintain homeostasis [59]. Sestrin 2 (SESN2) also play a role in the p62-dependent mitophagy [60]. Extended LPS stimulation upregulates the protein level of SESN2, which interacts with p62 to facilitate its aggregation on mitochondria. Besides, SESN2 activates the autophagic machinery by raising the ULK1 protein level [60]. Overall, the accumulation of damaged mitochondria is likely to result from both forward and reverse regulation of mitophagy. How these different mitophagic pathways are spatiotemporally coordinated in sepsis is still elusive. Given the critical role of damaged mitochondria in promoting immune response (which will be discussed in the later section), it is plausible that early-stage inhibition of mitophagy promotes the accumulation of dysfunctional mitochondria and benefit bacterial defense [54], while late-stage activation of mitophagy represents a cellular attempt to mitigate inflammation and restore host homeostasis [59].

Unlike in immune cells, the overall mitophagy in various organs is enhanced during sepsis. The heart samples from LPS-challenged mice have shown decreased mitochondrial number and volume, suggesting autophagic removal of mitochondria [29, 61]. Immunoblot analysis of kidney tissue from LPS or CLP-treated mice has shown a decrease in mitochondrial protein levels (TOM20 and TIM23) compared with control mice, providing substantial evidence that mitophagy is induced during the sepsis-caused acute kidney injury [62]. It was also demonstrated that the mitophagy is mainly mediated by the PINK1/Parkin/OPTN pathway [62]. Reductions of mitochondrial mass were also reported in the liver of CLP or LPS-treated septic mice [63]. These studies collectively suggest that mitophagy is enhanced in various organs during sepsis.

Mitochondrial dynamics

Mitochondria constantly undergo fusion and fission processes (Fig. 2b). Fusion forms interconnected mitochondrial networks, promoting content exchange, which is essential for the integrity of the mitochondrial genome and proteome. Conversely, fission fragments mitochondria, aiding in the elimination of dysfunctional parts [64, 65]. Dysregulation of mitochondrial dynamics is a crucial mechanism that induces mitochondrial stress [66].

During sepsis, excessive mitochondrial fragmentation happens in various tissues, revealing the change in mitochondrial dynamics [62, 67, 68]. To exploit the influence of mitochondrial fission in sepsis, Gonzalez et al. treated rats with the Drp1 inhibitor mdivi-1 before CLP administration. This treatment restored mitochondrial shape and prevented the reduction of complex activities and apoptosis in hepatocytes [68]. Similar beneficial effects of mdivi-1 have been confirmed in other studies [13, 69, 70]. Pharmacological administration of alternative fission inhibitors, such as P110 (inhibit Drp1/Fis1 interaction), also showed protection to mitochondria under septic stress [71, 72]. These findings demonstrate that excessive fission significantly contributes to the impairment of mitochondria during sepsis. Inhibition of this process, therefore, is an effective method to restore mitochondrial function.

Mitochondrial membrane permeabilization

Mitochondrial membrane pores cause mitochondrial swelling, content loss, and ΔΨm dissipation [73]. Three principal mechanisms involved in pore formation during sepsis are mitochondrial outer membrane permeabilization (MOMP), mitochondrial permeability transition (MPT), and more recently characterized gasdermins (GSDMs)-mediated mitochondrial membrane opening (Fig. 3).Fig. 3 Mechanisms of mitochondrial membrane permeabilization in sepsis. Three principal mechanisms are implicated in sepsis-related mitochondrial membrane pore formation. Mitochondrial outer membrane permeabilization (MOMP) is mediated by Bcl-2 family proteins Bax/Bak and regulated tBid. Large BAK/BAX pores allow the protrusion of IMM into the cytosol, therefore, enabling the escape of mitochondrial matrix contents. Mitochondrial permeability transition pore (MPTP) represents another type of mitochondrial pore in sepsis. Despite the opening mechanism of MPTP is still elusive, mitochondrial components such as F1FO (F)-ATP synthase, ANT, and Cyp-D have been confirmed to play pivotal roles in this process. Gasdermins (GSDMs) are well-known to form pores on plasma membrane during immune response. Recent advances have demonstrated that GSDMs target both the inner and outer mitochondrial membranes via their strong binding preference to cardiolipin. ROS promote the externalization of cardiolipin from IMM to OMM, thus, positively regulate GSDMs-mediate pore formation. Overall, mitochondrial membrane permeabilization leads to mitochondrial swelling, content loss, and dissipation of membrane potential during sepsis

MOMP is mediated by Bcl-2 family proteins Bax and Bak, which open the OMM in response to apoptotic signals. MOMP leads to mitochondrial damage and release of intermembrane space molecules like cytochrome C [74]. Large Bax/Bak pores also allow the IMM to protrude out of mitochondria, releasing matrix contents [75, 76]. Cytokines such as INF-γ and TNF-α could be recognized by the cell membrane death receptors, thereby activating caspase-8 during sepsis [77]. The activated caspase-8 cleaves Bid, generating a truncated form of Bid (tBid), which translocates to mitochondria and activates Bax/Bak to induce MOMP and cell death [78–80]. Chuang et al. have observed increased tBid in mitochondrial fractions of various tissues from the CLP-treated mouse, while Bid deficiency significantly reduced the downstream cell death [81]. In addition to caspase-8, caspase-1 has also been reported to cleave Bid and induce MOMP during the inflammatory response of macrophage [82].

The occurrence of MPT has been described in several septic models [83–86]. Pharmacological inhibition of MPT by cyclosporin A (CsA) can significantly attenuate mtDNA release and mitochondrial dysfunction in these models, suggesting MPT’s crucial role in sepsis-induced mitochondrial damage [83–85]. Although the exact molecular composition and mechanism of MPT remains a topic of ongoing research, key components are believed to include the F1FO (F)-ATP synthase, adenine nucleotide translocator (ANT), cyclophilin D (Cyp-D), and voltage-dependent anion channel (VDAC) [87]. These components assemble into a supramolecular pore (MPTP) at the interface of the IMM and OMM [88]. Elevated ROS levels can induce MPTP opening through oxidative modifications of MPT constituents or other mitochondrial proteins [89, 90].

GSDMs are key players in immune response, particularly in mediating pyroptosis. During inflammation, GSDMs are cleaved by caspases to release their active N-terminal fragments (GSDMs-N). GSDMs-N translocate to the plasma membrane, forming pores and disrupting the membrane [91]. Recent findings indicate that GSDMs also target mitochondrial membranes, representing a new pathway of mitochondrial permeabilization [92–97]. Time-lapse imaging analysis revealed that mitochondrial damage occurs much earlier than the opening of cell membrane, suggesting that GSDMs-N permeabilizes the mitochondria before cell membrane [92, 93]. This phenomenon has been attributed to the strong binding preference of GSDMs-N to mitochondrial cardiolipin [92]. Of note, ROS promote the externalization of cardiolipin from IMM to OMM, explaining the accumulation of GSDMD-N on OMM, as cardiolipin predominantly localizes in the IMM under normal conditions [95]. Overall, GSDM-mediated pore formation represents a novel pathway of mitochondrial permeabilization during immune response.

Damaged mitochondria are potent triggers of immune response and metabolic reprogramming

The innate immune response plays a key role in the pathophysiology of sepsis. Upon activation, pattern recognition receptors (PRRs) initiate signaling cascades, leading to the nuclear translocation of NF-κB, interferon regulatory factor (IRF), and other transcription factors. These transcription factors initiate the production of pro-inflammatory cytokines, chemokines, type I interferons (IFNs), etc. [98]. In the past few decades, damaged mitochondria have been widely demonstrated as a crucial regulator of innate immunity, particularly through the NLRP3, TLR9, and cGAS pathways. Thus, mitochondria damage is not simply a passive outcome under stress conditions, but actively contributes to the inflammatory response that is essential for the defense of pathogens. However, in the context of sepsis, excessive or persistent inflammation can cause a fatal inflammatory imbalance in the body, which ultimately leads to tissue and organ damage [99]. In this section, we will highlight the roles of mitochondria in regulating inflammatory pathways.

NLRP3 inflammasome pathway

NLRP3 inflammasome activation

The NLRP3 inflammasome activates pro-caspase-1, which cleaves pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) to promote their maturation [100]. Current studies, mainly in monocytes/macrophages, have revealed several regulatory roles of mitochondria in NLRP3 inflammasome activation. Mitochondrial ROS (mtROS) have been demonstrated as essential molecules for NLRP3 inflammasome activation. In sepsis models, inhibition of mtROS reduces the NLRP3 inflammasome-mediated cytokine production [101–103]. Several studies have provided insights into the mechanisms by which ROS modulate NLRP3 activation. In 2010, Zhou et al. identified thioredoxin (TRX)-interacting protein (TXNIP) as a binding partner of NLRP3. Under basal conditions, TXNIP binds to TRX, being unavailable to NLRP3. ROS promote NLRP3 activation by triggering the dissociation of TXNIP from TRX [104]. In another study, mtROS were confirmed to facilitate NLRP3 inflammasome activation through promoting its deubiquitination [105]. Interestingly, Bauernfeind and colleagues reported that ROS increase the NLRP3 expression instead of activating it, suggesting a translational regulation of NLRP3 by ROS [106].

mtDNA also regulates NLRP3 inflammasome activation. Nakahira et al. demonstrated that preventing MPT-mediated mtDNA release significantly reduces IL-1β secretion in macrophages after LPS + ATP challenge [83]. Interestingly, NLRP3 inflammasome is preferentially activated by oxidized mtDNA (ox-mtDNA), rather than normal mtDNA [107]. Zhong et al. found that TLR4 signalling promotes de novo mtDNA synthesis to sustain the generation of ox-mtDNA, since the newly synthesized mtDNA is not packaged and is highly susceptible to oxidation [108]. Before being released into cytosol, the ox-mtDNA undergoes a cleavage process to become 500–650 bp fragments. Xian et al. recently identified the flap structure-specific endonuclease 1 (FEN1) as the key mediator of this process [109]. AIM2 inflammasome can also be activated by the mtDNA. Unlike NLPR3 inflammasome, AIM2 inflammasome is activated by normal DNA to ox-mtDNA [107, 108].

Spatial association between mitochondria and NLRP3

The spatial association of NLRP3 inflammasome with organelles is critical for its activation. Early studies posited mitochondria or mitochondria-associated membrane (MAM) as the docking sites of NLRP3, while more recent publications have implicated trans-Golgi network (TGN) and microtubule-organizing center (MTOC) [110–114].

Zhou et al. reported that inflammatory stimuli trigger NLRP3 to co-localize with mitochondria and MAM in 2010 [112]. This spatial vicinity may facilitate the sensing of mitochondria-derived inflammatory signals [112, 115]. Microtubules also play a role in the mitochondria-NLRP3 association. Mechanistically, mitochondrial dysfunction during inflammation reduces NAD+ (oxidized form of nicotinamide adenine dinucleotide) generation, which in turn inhibits NAD+-dependent α-tubulin deacetylase sirtuin 2, leading to an increase in α-tubulin acetylation. The acetylated α-tubulin subsequently promoted dynein-dependent transport of mitochondria to NLRP3 [116]. Inflammatory stimuli also trigger the transport of NLRP3 towards mitochondria, which is orchestrated by microtubule-affinity regulating kinase 4 (MARK4). Depletion of MARK4 impairs NLRP3 spatial arrangement and inflammasome activation [111].

Mitochondrial antiviral-signaling protein (MAVS) and cardiolipin mediate the anchorage of NLRP3 on mitochondria [117–121]. MAVS lacking mitochondrial targeting domain cannot recruit NLRP3 or induce NLRP3 oligomerization, suggesting its mitochondrial localization is essential for NLRP3 inflammasome activation [120]. Given the well-established role of MAVS in recognizing virus RNA, it is plausible that microbial RNA plays a role in promoting the MAVS-dependent recruitment of NLRP3 during bacterial infection [121, 122]. In line with this, virus or Escherichia coli-induced activation of NLRP3 inflammasome was confirmed to greatly depend on MAVS [121], whereas LPS + ATP or LPS + nigericin (without microbial RNA) induced NLRP3 inflammasome activation is only partially affected by MAVS [117, 120, 121]. Cardiolipin also interacts with NLRP3 and contributes to the inflammasome activation [118]. A recent study suggested that cardiolipin recruits both NLRP3 and caspase-1, serving as a platform for inflammasome assembly [119].

Several recent publications have highlighted the involvement of Golgi apparatus and MTOC in NLRP3 inflammasome activation [113, 114, 123]. It is likely that NLRP3 protein is first transported to meet mitochondria along the microtubules, after which NLRP3 redistributes to the adjacent Golgi apparatus [115, 124]. Then, the NLRP3 is transported to the MTOC and reorganized into a single speck structure. At the MTOC, NLRP3 engages with NEK7, a centrosome-localized kinase that is essential for NLRP3 inflammasome activation (Fig. 4) [111, 114, 123, 125, 126].Fig. 4 Mitochondria-regulated inflammatory pathways in sepsis. Pattern recognition receptors (PRRs) of immune cells recognize pathogen-associated molecular patterns (PAMPs) from microbes or damage-associated molecular patterns (DAMPs) released by damaged host cells. a Mitochondria orchestrate the activation of the NLRP3 inflammasome. mtROS and ox-mtDNA promote the NLRP3 inflammasome activation after their release from the damaged mitochondria. Additionally, mitochondrial antiviral-signaling protein (MAVS) and cardiolipin mediate the spatial association between mitochondria and NLRP3, which may facilitate a rapid and efficient sensing of the inflammatory signals from the damaged mitochondria by NLRP3. Early studies posited mitochondria or mitochondria-associated membrane (MAM) as the docking sites of NLRP3, while more recent publications have indicated the involvement of Golgi and microtubule-organizing center (MTOC). It could be plausible that NLRP3 proteins are first transported to meet mitochondria, after which NLRP3 redistributes to the adjacent Golgi apparatus as oligomeric cages. Then, the NLRP3 cages are transported to MTOC and reorganized into a single inflammasome speck. Activated NLRP3 inflammasome mediates the activation of pro-caspase-1, which proteolytically processes GSDMs and pro-inflammatory cytokines. The matured cytokines are released from the GSDMs pores to transmit inflammatory signals. b Mitochondria regulate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cGAS is activated upon mtDNA binding, leading to the synthesis of cyclic GMP-AMP (cGAMP). cGAMP then induces a conformational change in STING, leading to its activation at ER. Activated STING translocates to Golgi, where it activates transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) to initiate the production of type I interferons and other pro-inflammatory cytokines that are required for effective immune response against pathogens. c Mitochondria regulate the TLR9 pathway. mtDNA shares similarities with bacterial DNA, thus can be recognized by TLR9. As with other TLRs and cGAS-STING axis, TLR9 pathway activates IRF3 and NF-κB to regulate the inflammatory response

cGAS-STING pathway activation

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is another mitochondria-regulated inflammatory pathway. cGAS detects cytosolic double-stranded DNA and initiates an innate immune response [127] (Fig. 4). Both normal and oxidized mtDNA can be recognized by cGAS [128], but ox-mtDNA is more resistant to degradation by the cytosolic nuclease 3' repair exonuclease 1, increasing its likelihood of interaction with cGAS [129].

In the CLP mouse model, Huang et al. have demonstrated that mtDNA can be released via the GSDMD pore to activate cGAS-STING pathway [94]. This pathway not only enhances the inflammatory response but also suppresses lung endothelial cell proliferation, which compromises the recovery capacity of host. Notably, the deletion of cGas gene provided mice with substantial protection from lung injury 72 h post-CLP, suggesting that cGAS-STING pathway is crucial in septic lung inflammation [94].

Studies have shown that circulating cell-free mtDNA levels are elevated in septic patients and animal models, correlating with poor prognosis [130–133]. Like cytosolic mtDNA, circulating mtDNA activates the cGAS-STING pathway and promotes inflammation during sepsis [133]. In CLP mice, the mtDNA-cGAS-STING signal promotes intestinal inflammation and gut barrier dysfunction, which could be significantly attenuated by removing circulating mtDNA with DNase I [134]. Mechanistically, host nuclear DNA, mtDNA and bacterial DNA can be recognized by cGAS, while to what extent mtDNA contributes to the cGAS-STING pathway activation awaits investigation [135, 136].

TLR9 pathway activation

TLR9 is initially known for sensing unmethylated CpG DNA motifs (consisting of a central cytosine-guanine dinucleotide plus flanking regions) from bacterial and viral DNA during innate immune response [137, 138]. However, a subsequent study suggests that TLR9 also recognizes endogenous mtDNA, which shares similarities with bacterial DNA [139]. This interaction stands for another inflammatory pathway regulated by mitochondria in sepsis (Fig. 4).

Experimental models have shown that intravenous administration of mitochondrial debris can elicit an immune response comparable to that of CLP treatment. However, Tlr9 knockout (KO) or DNase pretreatment of the mitochondrial debris greatly attenuates the inflammatory response, suggesting the crucial role of the mtDNA-TLR9 axis in sepsis [140]. In line with this, TLR9 inhibitor OND-I suppresses caspase 1 activation and IL–1β production in LPS-challenged cardiomyocytes [38]. Moreover, Tlr9 KO reduced renal dysfunction and splenic apoptosis after CLP treatment, and increased survival at 96 h [141]. Interestingly, Plitas and colleagues found that Tlr9 KO mice exhibited better bacterial clearance and greater survival than wide type (WT) mice after CLP treatment. The protective effects were associated with increased recruitment of granulocytes to the peritoneum by dendritic cells (DCs) [142]. These findings suggest that TLR9 might have a major role in the immunopathogenesis of polymicrobial sepsis compared to other TLRs [142].

Metabolic reprogramming

During sepsis, a widespread alteration in the metabolic pattern occurs in virtually all cell types, leading to a shift from oxidative phosphorylation (OXPHOS) to glycolysis—a phenomenon known as “metabolic reprogramming” [143]. The metabolic reprogramming is driven by the downregulation of OXPHOS due to mitochondrial dysfunction and the upregulation of glycolysis through the enhancement of glycolytic pathways [144]. This shift in metabolism profoundly affects immune response and organ function in sepsis.

In the immune context, glycolysis, albeit less efficient than OXPHOS, allows rapid generation of ATP and synthesis of metabolic intermediates necessary for immune cell activation and proliferation [145]. Glycolytic inhibitors, such as 2-deoxyglucose (2-DG), have been shown to reduce systemic inflammation in sepsis, indicating their potential in therapeutic interventions [146, 147]. The metabolic reprogramming is also implicated in the development MOF. An early histopathologic study of patients dying of sepsis has revealed that the actual cell death in most organs is minimal, despite severe clinical signs of MOF [148]. This observation indicates that the organ failure is functional rather than structural [149]. Given that mitochondrial dysfunction results in less efficient ATP production, cells in affected organs face an energy crisis during sepsis. Consequently, metabolic reprogramming and the resultant bioenergetic failure are recognized as critical contributors to MOF in sepsis [150]. A key question regarding MOF in sepsis is whether it represents an adaptive or maladaptive event. Singer et al. have suggested that sepsis-induced MOF might be an adaptation by the host to increase the chances of cell survival against the infection. This response mirrors a state of “hibernation” in which non-essential functions are downregulated [9, 149].

Mitochondria-based therapeutic interventions

Effective treatments are crucial for aiding critically ill patients with sepsis. Previous research has shown that sepsis survivors responded early to the illness with induction of mitochondrial biogenesis and antioxidant defense, indicating the potential of maintaining mitochondrial homeostasis for sepsis therapy [19].

Antioxidants

Given the roles of ROS in triggering mitochondrial damage and inflammation, antioxidants have been extensively studied as therapeutic agents against sepsis. Mitochondria-targeted antioxidants have shown better effects on reducing inflammation compared to the untargeted equivalents [101, 151, 152]. The most frequently used mitochondria-specific antioxidants include MitoQ, MitoVitE, and MitoTempol (Fig. 5) [153].Fig. 5 Mitochondria-based therapeutic interventions. Mitochondria-targeted antioxidants such as MitoQ, MitoVitE, and MitoTempol are selectively targeted to mitochondria by conjugating to a lipophilic cation decyl-triphenylphosphonium (TPP+). The positive charge of cation enables the molecules to accumulate in mitochondrial matrix, therefore, specifically quench the mitochondrial ROS. Non-antioxidants Urolithin A, Mdivi-1, and Cyclosporin A improve mitochondrial quality by promoting mitophagy, inhibiting mitochondrial fission, and blocking MPTP, respectively. Metformin plays multiple roles on mitochondria, including enhancing mitophagy, reducing mtROS, preventing ox-mtDNA production, and inhibiting mitochondrial protein translation. These compounds target different aspects of mitochondria and exhibit great potential in reducing sepsis-induced mitochondrial damage, excessive inflammation, and organ dysfunction

MitoQ

MitoQ is synthesized by conjugating ubiquinone with the lipophilic cation decyl-triphenylphosphonium (TPP+). Although it has not received approval from the U.S. Food and Drug Administration (FDA), MitoQ has been the subject of several clinical trials aiming to explore its potential benefits for treating oxidative pathologies [154]. Lowes et al. demonstrated that MitoQ protects mitochondria during sepsis, and suppresses pro-inflammatory cytokine release, leading to reduced acute liver and renal dysfunction [102]. The beneficial effects have also been confirmed in other organs, including the lung, intestinal barrier, skeletal muscle, and heart, leading to the increased survival rate of septic animals [12, 155–157]. Notably, MitoQ treatment 6 h after sepsis induction yielded comparable outcomes in comparison with immediate treatment in the diaphragm muscle. This property makes MitoQ a good candidate for clinical application, considering the typical delay between sepsis onset and treatment initiation [157].

MitoVitE

MitoVitE is a modified form of vitamin E, attached to the TPP+ [158]. Zang et al. examined its effects on cardiac dysfunction in a rat pneumonia-related sepsis model, and confirmed that a single dose of MitoVitE protected cardiac mitochondria, suppressed cytokine burst, and neutrophil infiltration in the myocardium, ultimately improving the cardiac function [101]. Another study using LPS/peptidoglycan (PepG)-induced sepsis rat model revealed that MitoVitE offers similar protection as MitoQ in improving mitochondrial health, mitigating inflammation, and reducing organ dysfunction [159].

MitoTempol

MitoTempol, constructed by combining the piperidine nitroxide (Tempol) with TPP+, is another mitochondria-targeted antioxidant [160]. In a rat model of fecal peritonitis, MitoTempol administration reduced IL-1β level, renal oxidative stress, and improved renal function [161]. Interestingly, while this study showed no beneficial effect on the core body temperature and survival rate [161], another investigation revealed that even a 6 h delayed MitoTempol therapy significantly improved core body temperature and increased the survival rate from 40 to 83% in CLP mice [35]. These contradictory results may be related to MitoTempol dosage. Insufficient dosing may fail to provide benefits, whereas excessive dosing may lead to over-accumulation of this cationic agent, resulting in mitochondrial damage [35]. Thus, fine-tuning the dosage is essential to minimize side effects and maximize therapeutic benefits.

NAD+

NAD+ is known for its functions in redox metabolism, immune response, aging, and DNA repair [162]. NAD+ shortage occurs during sepsis, prompting the exploration of NAD+ supplementation as a potential therapeutic strategy [163, 164]. NAD+ precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), are emerging as novel candidates for sepsis treatment. These precursors, naturally present in food and widely used as health supplements, have shown potential in preclinical studies by mitigating mitochondrial dysfunction, oxidative stress, inflammatory response, and multiorgan injury associated with sepsis [164–166]. The precise regulatory mechanisms of NAD+ in sepsis remain incompletely understood. As a critical co-enzyme, NAD+ plays a role in alleviating oxidative stress, in part through the activation of sirtuins, like Sirt3, a mitochondria-localized sirtuin [164, 165].

Non-antioxidants

Several non-antioxidant agents targeting mitophagy, mitochondrial dynamics, mitochondrial permeabilization, and other pathways have been reported to mitigate sepsis (Fig. 5).

Urolithin A

Urolithin A (UA) is a natural anti-aging compound known for inducing mitophagy [167]. It has attracted significant attention for the role in regulating inflammation [168, 169]. Two clinical trials in elderly individuals have shown that UA is safe, bioavailable, and well-tolerated [170, 171].

UA has been reported to sustain mitochondrial health in cardiomyocytes challenged with LPS in vitro [172]. In mice, UA administration alleviated the LPS-induced cardiac depression [173]. Interestingly, this protection was diminished upon FUNDC1 knockout, indicating UA activates mitophagy in a FUNDC1-dependent manner [173]. UA pre-administration was also found to alleviate pulmonary injury upon LPS challenge, and improve the survival rate [174]. Overall, while research on UA for sepsis treatment is still nascent, the existing evidence suggests significant therapeutic potential. Future research using more appropriate sepsis models would be recommended, as LPS treatment does not recapitulate the complex pathophysiological consequence of human sepsis [175, 176].

Mdivi-1

Mdivi-1 was first identified as an inhibitor of mitochondrial fission via chemical screening in 2008, [177]. Thereafter, numerous articles have been published on Mdivi-1, confirming its potency in inhibiting mitochondrial fission, improving mitochondrial health, and protecting cells from stress under various circumstances [178]. The wide application of Mdivi-1 promotes the development of novel therapeutic strategies for mitochondria-related diseases, including sepsis.

Mdivi-1 was shown to protect liver and brain function in the CLP mice model [179, 180]. Moreover, Zhu et al. showed that Mdivi-1 significantly restored the function of multiple organs in CLP-treated rats, and extended the average survival time from 8.83 h to 60.3 h. In this study, Mdivi-1 was administered 12 h after sepsis, which mirrors a clinically relevant scenario [13]. Other fission inhibitors, like P100 and irisin, have also been reported to mitigate organ injury and reduce mortality after sepsis [71, 72, 181].

Cyclosporin A

CsA is an FDA approved compound that has been utilized as an anti-inflammatory drug to treat ocular surface diseases [182]. Cyclosporin A has been widely used as an immunosuppressant to prevent immune responses against transplanted organs in clinic [183]. CsA potentially inhibits immune response via two pathways. First, CsA inhibits MPTP by interacting with Cyp-D, thus, reducing DAMPs release from mitochondria [184]. Second, CsA forms a complex with cyclophilin A to inhibit calcineurin. This inhibition thereafter impairs the nuclear translocation of nuclear factor of activated T cells (NFAT) and NFκB in immune cells, leading to reduced production of iNOS, inflammatory cytokines and prostaglandins [185].

Over the past two decades, CsA has been reported to attenuate mtDNA release and mitochondrial damage in various septic models [83–85, 186]. These studies confirmed the protective effects of CsA on sepsis-induced organ dysfunction and mortality [83–85, 186]. CsA and NIM811 (a cyclophilin non-binding derivate of CsA that inhibits MPTP) rather than tacrolimus (a potent immunosuppressive compound which does not inhibit MPTP) provided protection against septic insult, suggesting that the beneficial effects of CsA were predominantly related to the inhibition of MPTP [84, 187]. However, Joshi et al. reported that tacrolimus provided similar cardiac protection as CsA upon LPS treatment [188]. This discrepancy maybe due to the severity of mitochondrial injury; CsA's MPTP inhibitory function becomes critical only when mitochondrial damage is severe.

Metformin

Metformin has been widely used to treat type 2 diabetes, whose clinical experience and trial data have raised almost no safety concerns [189, 190]. Several studies have highlighted the capacity of metformin in combating sepsis. For instance, Liu et al. demonstrated that metformin prevents excessive inflammation and the development of immunosuppression, increasing bacterial clearance in the lungs of septic mice [191]. Metformin also preserves brain, lung, liver, and colon barrier function by suppressing sepsis-induced inflammatory responses in animal models [192–194]. In human patients, several retrospective studies have been performed to evaluate the effect of metformin on sepsis. However, some of these studies revealed that metformin users (mainly diabetic patients) had lower in-hospital mortality than nonusers [195–197], while others showed that pre-admission of metformin did not change the mortality in septic patients [198, 199]. Two meta-analyses on these published cohort data were, therefore, performed to confirm the contribution of metformin in the mortality in septic adult patients. The results supported the positive effect of metformin in lowering the mortality of sepsis [200, 201]. Recently, three clinical trials (NCT05979038, NCT06181422, NCT05900284) evaluating the efficiency and safety of metformin in sepsis patients are ongoing, which will improve our understanding about the clinical feasibility of metformin in sepsis therapy.

The pharmacological mechanisms of metformin are multifaceted. Metformin regulates inflammation through both AMPK-dependent and independent pathways [202]. Mechanistically, metformin activates AMPK and suppresses the nutrient sensor mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which promotes autophagy. Autophagic elimination of damaged mitochondria subsequently limits NLRP3 inflammasome activation [203, 204]. AMPK also phosphorylate the PGC-1α to promote mitochondrial biogenesis [205]; or regulate transcription factors to reduce ROS and cytokine production [206, 207]. The activation of AMPK by metformin appears to be dose-dependent: Low-dose metformin drives AMPK activation through the lysosomal pathway, while high-dose metformin takes effect by inhibiting the complex I of respiratory chain, resulting in ATP shortage [208]. Xian et al. have revealed that the metformin-triggered ATP shortage can prevent the production of ox-mtDNA, thus, reducing NLRP3 inflammasome activation [204]. Metformin also diminishes IL-6 secretion, likely via the suppression of JNK and p38 MAPK [204]. Very recently, Marlies Cortés and colleagues uncovered that metformin’s anti-inflammatory effects rely on the expression of ZEB1, which restricts amino acid uptake, thereby downregulating the mTORC1 signaling and mitochondrial protein translation, leading to the inhibition of both acute and chronic inflammation [209].

Conclusion

Sepsis is a significant medical challenge characterized by a systemic inflammatory response. During sepsis, factors such as RNS/ROS, impaired mitophagy, altered mitochondrial dynamics, and membrane permeabilization result in the accumulation of defective mitochondria in immune cells and tissues. These damaged mitochondria promote the immune response via key pathways governed by NLRP3, TLR9, and cGAS. Preclinical studies have identified several agents that target mitochondrial quality control to reduce mitochondrial damage. These agents effectively attenuate inflammation and mortality, offering a novel approach for sepsis treatment.

Abbreviations

AKI Acute kidney injury

ALI Acute lung injury

AMPK AMP-activated protein kinase

ANT Adenine nucleotide translocator

BNIP3 BCL2 interacting protein3

CALCOCO2/NDP52 Calcium binding and coiled-coil domain-containing protein 2

CASP Colon ascendens stent peritonitis

cGAS Cyclic GMP-AMP synthase

CLP Cecal ligation and puncture

CsA Cyclosporin A

Cyp-D Cyclophilin D

DAMPs Damage-associated molecular patterns

DCs Dendritic cells

Drp1 Dynamin-related protein 1

ER Endoplasmic reticulum

ETC Electron transport chain

FDA U.S. food and drug administration

FEN1 Flap structure-specific endonuclease 1

Fis1 Fission 1

FUNDC1 FUN14 domain containing 1

GSDMs Gasdermins

ICUs Intensive care units

IFNs Interferons

IL Interleukin

IMS Intermembrane space

IRF Interferon regulatory factor

KO Knockout

LC3 Microtubule-associated protein 1 light chain 3

L-OPA1 Long OPA1 isoforms

LPS Lipopolysaccharides

MAM Mitochondria-associated membrane

MARK4 Microtubule-affinity regulating kinase 4

MAVS Mitochondrial antiviral-signaling protein

Mff Mitochondrial fusion factor

Mfn1/2 Mitofusin 1/2

MOF Multi-organ failure

MOMP Mitochondrial outer membrane permeabilization

MPT Mitochondrial permeability transition

mtDNA Mitochondrial DNA

MTOC Microtubule-organizing center

mTOR Mammalian target of rapamycin

mtROS Mitochondrial ROS

NADH Nicotinamide adenine dinucleotide dehydrogenase

NBR1 Next to BRCA1 gene 1 protein

NFAT Nuclear factor of activated T cells

NF-κB Nuclear factor κB

NIX Nip3-like protein X

NLRs NOD-like receptors

NOXs Nicotinamide adenine dinucleotide phosphate oxidases

OMM Outer mitochondrial membrane

OPA1 Optic atrophy 1

OPTN Optineurin

ox-mtDNA Oxidized mitochondrial DNA

PAMPs Pathogen-associated molecular patterns

PBMCs Peripheral blood mononuclear cells

PepG Peptidoglycan

PGC-1 β Peroxisome-proliferator-activated receptor γ coactivator 1 β

PHB Prohibitin

PINK1 PTEN-induced kinase 1

PRRs Pattern recognition receptors

RNS Reactive nitrogen species

SESN2 Sestrin 2

S-OPA1 Short OPA1 isoforms

STING Stimulator of interferon genes

STX17 Syntaxin 17

TAX1BP1 Tax1-binding protein 1

tBid Truncated form of Bid

TCA Tricarboxylic acid

Tempol Piperidine nitroxide

TFAM Mitochondrial transcription factor A

TGN Trans-Golgi network

TLRs Toll-like receptors

TPP+ Decyl-triphenylphosphonium

TRX Thioredoxin

TXNIP Thioredoxin-interacting protein

UA Urolithin A

UCPs Uncoupling proteins

ULK1 Unc-51 like autophagy activating kinase 1

VDAC Voltage-dependent anion channel

WT Wide type

ΔΨm Mitochondrial membrane potential

Acknowledgements

Figures used in this review are made in BioRender.com.

Author contributions

Dongxue Hu and Harshini Sheeja Prabhakaran contributed to the data collection of the article. Dongxue Hu, Harshini Sheeja Prabhakaran, Weifeng He, and Yih-Cherng Liou contributed to the conception, preparation and organization of this article. Yuan-Yuan Zhang and Gaoxing Luo contributed to the organization and constructive discussions. Weifeng He and Yih-Cherng Liou revised the draft of the manuscript.

Funding

This work is financially supported by MOE Tier2 and Tier1 (A-8000985 and A-8000412) grants from the Ministry of Education (MOE), Singapore, awarded to Y-C. Liou.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dongxue Hua and Harshini Sheeja Prabhakaran contributed equally to this work.
==== Refs
References

1. Singer M Deutschman CS Seymour CW Shankar-Hari M Annane D Bauer M Bellomo R Bernard GR Chiche JD Coopersmith CM The third international consensus definitions for sepsis and septic shock (sepsis-3) JAMA 2016 315 8 801 810 10.1001/jama.2016.0287 26903338
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10.26903338 10.1001/jama.2016.0287
2. Rudd KE Johnson SC Agesa KM Shackelford KA Tsoi D Kievlan DR Colombara DV Ikuta KS Kissoon N Finfer S Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study Lancet 2020 395 10219 200 211 10.1016/S0140-6736(19)32989-7 31954465
Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11.31954465 10.1016/S0140-6736(19)32989-7
3. Srzic I Nesek Adam V Tunjic Pejak D Sepsis definition: what's new in the treatment guidelines Acta Clin Croat 2022 61 Suppl 1 67 72 36304809
Srzic I, Nesek Adam V, Tunjic Pejak D. Sepsis definition: what’s new in the treatment guidelines. Acta Clin Croat. 2022;61(Suppl 1):67–72.36304809
4. Misrani A Tabassum S Yang L Mitochondrial dysfunction and oxidative stress in Alzheimer's disease Front Aging Neurosci 2021 13 617588 10.3389/fnagi.2021.617588 33679375
Misrani A, Tabassum S, Yang L. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease. Front Aging Neurosci. 2021;13:617588.33679375 10.3389/fnagi.2021.617588
5. Schenkel LC Bakovic M Formation and regulation of mitochondrial membranes Int J Cell Biol 2014 2014 709828 10.1155/2014/709828 24578708
Schenkel LC, Bakovic M. Formation and regulation of mitochondrial membranes. Int J Cell Biol. 2014;2014:709828.24578708 10.1155/2014/709828
6. Vercellino I Sazanov LA The assembly, regulation and function of the mitochondrial respiratory chain Nat Rev Mol Cell Biol 2022 23 2 141 161 10.1038/s41580-021-00415-0 34621061
Vercellino I, Sazanov LA. The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol. 2022;23(2):141–61.34621061 10.1038/s41580-021-00415-0
7. Kong C Song W Fu T Systemic inflammatory response syndrome is triggered by mitochondrial damage (review) Mol Med Rep 2022 25 4 1 8 10.3892/mmr.2022.12663 34726254
Kong C, Song W, Fu T. Systemic inflammatory response syndrome is triggered by mitochondrial damage (review). Mol Med Rep. 2022;25(4):1–8.34726254 10.3892/mmr.2022.12663
8. Lira Chavez FM Gartzke LP van Beuningen FE Wink SE Henning RH Krenning G Bouma HR Restoring the infected powerhouse: Mitochondrial quality control in sepsis Redox Biol 2023 68 102968 10.1016/j.redox.2023.102968 38039825
Lira Chavez FM, Gartzke LP, van Beuningen FE, Wink SE, Henning RH, Krenning G, Bouma HR. Restoring the infected powerhouse: Mitochondrial quality control in sepsis. Redox Biol. 2023;68:102968.38039825 10.1016/j.redox.2023.102968
9. Singer M The role of mitochondrial dysfunction in sepsis-induced multi-organ failure Virulence 2014 5 1 66 72 10.4161/viru.26907 24185508
Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5(1):66–72.24185508 10.4161/viru.26907
10. Zhang W Jiang H Wu G Huang P Wang H An H Liu S Zhang W The pathogenesis and potential therapeutic targets in sepsis MedComm (2020) 2023 4 6 e418 38020710
Zhang W, Jiang H, Wu G, Huang P, Wang H, An H, Liu S, Zhang W. The pathogenesis and potential therapeutic targets in sepsis. MedComm (2020). 2023;4(6):e418.38020710
11. Marchi S Guilbaud E Tait SWG Yamazaki T Galluzzi L Mitochondrial control of inflammation Nat Rev Immunol 2023 23 3 159 173 10.1038/s41577-022-00760-x 35879417
Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2023;23(3):159–73.35879417 10.1038/s41577-022-00760-x
12. Li R Ren T Zeng J Mitochondrial coenzyme Q protects sepsis-induced acute lung injury by activating PI3K/Akt/GSK-3beta/mTOR pathway in rats Biomed Res Int 2019 2019 5240898 10.1155/2019/5240898 31815144
Li R, Ren T, Zeng J. Mitochondrial coenzyme Q protects sepsis-induced acute lung injury by activating PI3K/Akt/GSK-3beta/mTOR pathway in rats. Biomed Res Int. 2019;2019:5240898.31815144 10.1155/2019/5240898
13. Zhu Y Kuang L Wu Y Deng H She H Zhou Y Zhang J Liu L Li T Protective effects of inhibition of mitochondrial fission on organ function after sepsis Front Pharmacol 2021 12 712489 10.3389/fphar.2021.712489 34566637
Zhu Y, Kuang L, Wu Y, Deng H, She H, Zhou Y, Zhang J, Liu L, Li T. Protective effects of inhibition of mitochondrial fission on organ function after sepsis. Front Pharmacol. 2021;12:712489.34566637 10.3389/fphar.2021.712489
14. Tzanavari T Varela A Theocharis S Ninou E Kapelouzou A Cokkinos DV Kontaridis MI Karalis KP Metformin protects against infection-induced myocardial dysfunction Metabolism 2016 65 10 1447 1458 10.1016/j.metabol.2016.06.012 27621180
Tzanavari T, Varela A, Theocharis S, Ninou E, Kapelouzou A, Cokkinos DV, Kontaridis MI, Karalis KP. Metformin protects against infection-induced myocardial dysfunction. Metabolism. 2016;65(10):1447–58.27621180 10.1016/j.metabol.2016.06.012
15. Japiassu AM Santiago AP d'Avila JC Garcia-Souza LF Galina A Castro Faria-Neto HC Bozza FA Oliveira MF Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5'-triphosphate synthase activity Crit Care Med 2011 39 5 1056 1063 10.1097/CCM.0b013e31820eda5c 21336129
Japiassu AM, Santiago AP, d’Avila JC, Garcia-Souza LF, Galina A, Castro Faria-Neto HC, Bozza FA, Oliveira MF. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5’-triphosphate synthase activity. Crit Care Med. 2011;39(5):1056–63.21336129 10.1097/CCM.0b013e31820eda5c
16. Garrabou G Moren C Lopez S Tobias E Cardellach F Miro O Casademont J The effects of sepsis on mitochondria J Infect Dis 2012 205 3 392 400 10.1093/infdis/jir764 22180620
Garrabou G, Moren C, Lopez S, Tobias E, Cardellach F, Miro O, Casademont J. The effects of sepsis on mitochondria. J Infect Dis. 2012;205(3):392–400.22180620 10.1093/infdis/jir764
17. Protti A Fortunato F Artoni A Lecchi A Motta G Mistraletti G Novembrino C Comi GP Gattinoni L Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock Crit Care 2015 19 1 39 10.1186/s13054-015-0762-7 25757508
Protti A, Fortunato F, Artoni A, Lecchi A, Motta G, Mistraletti G, Novembrino C, Comi GP, Gattinoni L. Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock. Crit Care. 2015;19(1):39.25757508 10.1186/s13054-015-0762-7
18. Fredriksson K Rooyackers O Mitochondrial function in sepsis: respiratory versus leg muscle Crit Care Med 2007 35 9 Suppl S449 453 10.1097/01.CCM.0000278048.00896.4B 17713392
Fredriksson K, Rooyackers O. Mitochondrial function in sepsis: respiratory versus leg muscle. Crit Care Med. 2007;35(9 Suppl):S449-453.17713392 10.1097/01.CCM.0000278048.00896.4B
19. Carre JE Orban JC Re L Felsmann K Iffert W Bauer M Suliman HB Piantadosi CA Mayhew TM Breen P Survival in critical illness is associated with early activation of mitochondrial biogenesis Am J Respir Crit Care Med 2010 182 6 745 751 10.1164/rccm.201003-0326OC 20538956
Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med. 2010;182(6):745–51.20538956 10.1164/rccm.201003-0326OC
20. Soriano FG Nogueira AC Caldini EG Lins MH Teixeira AC Cappi SB Lotufo PA Bernik MM Zsengeller Z Chen M Potential role of poly(adenosine 5'-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock Crit Care Med 2006 34 4 1073 1079 10.1097/01.CCM.0000206470.47721.8D 16484919
Soriano FG, Nogueira AC, Caldini EG, Lins MH, Teixeira AC, Cappi SB, Lotufo PA, Bernik MM, Zsengeller Z, Chen M, et al. Potential role of poly(adenosine 5’-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit Care Med. 2006;34(4):1073–9.16484919 10.1097/01.CCM.0000206470.47721.8D
21. Kingsley SM Bhat BV Differential paradigms in animal models of sepsis Curr Infect Dis Rep 2016 18 9 26 10.1007/s11908-016-0535-8 27432263
Kingsley SM, Bhat BV. Differential paradigms in animal models of sepsis. Curr Infect Dis Rep. 2016;18(9):26.27432263 10.1007/s11908-016-0535-8
22. Singer M Brealey D Mitochondrial dysfunction in sepsis Biochem Soc Symp 1999 66 149 166 10.1042/bss0660149 10989665
Singer M, Brealey D. Mitochondrial dysfunction in sepsis. Biochem Soc Symp. 1999;66:149–66.10989665 10.1042/bss0660149
23. Corrêa TD Jakob SM Takala J Mitochondrial function in sepsis Crit Care Horizons 2015 1 31 41
Corrêa TD, Jakob SM, Takala J. Mitochondrial function in sepsis. Crit Care Horizons. 2015;1:31–41.
24. Brealey D Karyampudi S Jacques TS Novelli M Stidwill R Taylor V Smolenski RT Singer M Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure Am J Physiol Regul Integr Comp Physiol 2004 286 3 R491 497 10.1152/ajpregu.00432.2003 14604843
Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R491-497.14604843 10.1152/ajpregu.00432.2003
25. Gellerich FN Trumbeckaite S Hertel K Zierz S Müller-Werdan U Werdan K Redl H Schlag G Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain Shock (Augusta, GA) 1999 11 5 336 341 10.1097/00024382-199905000-00006 10353539
Gellerich FN, Trumbeckaite S, Hertel K, Zierz S, Müller-Werdan U, Werdan K, Redl H, Schlag G. Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain. Shock (Augusta, GA). 1999;11(5):336–41.10353539 10.1097/00024382-199905000-00006
26. Brealey D Singer M Mitochondrial dysfunction in sepsis Curr Infect Dis Rep 2003 5 5 365 371 10.1007/s11908-003-0015-9 13678565
Brealey D, Singer M. Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep. 2003;5(5):365–71.13678565 10.1007/s11908-003-0015-9
27. Boulos M Astiz ME Barua RS Osman M Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase Crit Care Med 2003 31 2 353 358 10.1097/01.CCM.0000050074.82486.B2 12576936
Boulos M, Astiz ME, Barua RS, Osman M. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med. 2003;31(2):353–8.12576936 10.1097/01.CCM.0000050074.82486.B2
28. Fredriksson K Hammarqvist F Strigard K Hultenby K Ljungqvist O Wernerman J Rooyackers O Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure Am J Physiol Endocrinol Metab 2006 291 5 E1044 1050 10.1152/ajpendo.00218.2006 16803854
Fredriksson K, Hammarqvist F, Strigard K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O. Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Am J Physiol Endocrinol Metab. 2006;291(5):E1044-1050.16803854 10.1152/ajpendo.00218.2006
29. Li Y Feng YF Liu XT Li YC Zhu HM Sun MR Li P Liu B Yang H Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis Redox Biol 2021 38 101771 10.1016/j.redox.2020.101771 33189984
Li Y, Feng YF, Liu XT, Li YC, Zhu HM, Sun MR, Li P, Liu B, Yang H. Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis. Redox Biol. 2021;38:101771.33189984 10.1016/j.redox.2020.101771
30. Tran M Tam D Bardia A Bhasin M Rowe GC Kher A Zsengeller ZK Akhavan-Sharif MR Khankin EV Saintgeniez M PGC-1alpha promotes recovery after acute kidney injury during systemic inflammation in mice J Clin Invest 2011 121 10 4003 4014 10.1172/JCI58662 21881206
Tran M, Tam D, Bardia A, Bhasin M, Rowe GC, Kher A, Zsengeller ZK, Akhavan-Sharif MR, Khankin EV, Saintgeniez M, et al. PGC-1alpha promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest. 2011;121(10):4003–14.21881206 10.1172/JCI58662
31. Choumar A Tarhuni A Letteron P Reyl-Desmars F Dauhoo N Damasse J Vadrot N Nahon P Moreau R Pessayre D Lipopolysaccharide-induced mitochondrial DNA depletion Antioxid Redox Signal 2011 15 11 2837 2854 10.1089/ars.2010.3713 21767162
Choumar A, Tarhuni A, Letteron P, Reyl-Desmars F, Dauhoo N, Damasse J, Vadrot N, Nahon P, Moreau R, Pessayre D, et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid Redox Signal. 2011;15(11):2837–54.21767162 10.1089/ars.2010.3713
32. Hansen ME Simmons KJ Tippetts TS Thatcher MO Saito RR Hubbard ST Trumbull AM Parker BA Taylor OJ Bikman BT Lipopolysaccharide disrupts mitochondrial physiology in skeletal muscle via disparate effects on sphingolipid metabolism Shock 2015 44 6 585 592 10.1097/SHK.0000000000000468 26529656
Hansen ME, Simmons KJ, Tippetts TS, Thatcher MO, Saito RR, Hubbard ST, Trumbull AM, Parker BA, Taylor OJ, Bikman BT. Lipopolysaccharide disrupts mitochondrial physiology in skeletal muscle via disparate effects on sphingolipid metabolism. Shock. 2015;44(6):585–92.26529656 10.1097/SHK.0000000000000468
33. d'Avila JC Santiago AP Amancio RT Galina A Oliveira MF Bozza FA Sepsis induces brain mitochondrial dysfunction Crit Care Med 2008 36 6 1925 1932 10.1097/CCM.0b013e3181760c4b 18496362
d’Avila JC, Santiago AP, Amancio RT, Galina A, Oliveira MF, Bozza FA. Sepsis induces brain mitochondrial dysfunction. Crit Care Med. 2008;36(6):1925–32.18496362 10.1097/CCM.0b013e3181760c4b
34. Kokkinaki D Hoffman M Kalliora C Kyriazis ID Maning J Lucchese AM Shanmughapriya S Tomar D Park JY Wang H Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy J Mol Cell Cardiol 2019 127 232 245 10.1016/j.yjmcc.2018.12.016 30611795
Kokkinaki D, Hoffman M, Kalliora C, Kyriazis ID, Maning J, Lucchese AM, Shanmughapriya S, Tomar D, Park JY, Wang H, et al. Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy. J Mol Cell Cardiol. 2019;127:232–45.30611795 10.1016/j.yjmcc.2018.12.016
35. Patil NK Parajuli N MacMillan-Crow LA Mayeux PR Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury Am J Physiol Renal Physiol 2014 306 7 F734 743 10.1152/ajprenal.00643.2013 24500690
Patil NK, Parajuli N, MacMillan-Crow LA, Mayeux PR. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury. Am J Physiol Renal Physiol. 2014;306(7):F734-743.24500690 10.1152/ajprenal.00643.2013
36. Vanasco V Saez T Magnani ND Pereyra L Marchini T Corach A Vaccaro MI Corach D Evelson P Alvarez S Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery Free Radic Biol Med 2014 77 1 9 10.1016/j.freeradbiomed.2014.08.009 25224040
Vanasco V, Saez T, Magnani ND, Pereyra L, Marchini T, Corach A, Vaccaro MI, Corach D, Evelson P, Alvarez S. Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery. Free Radic Biol Med. 2014;77:1–9.25224040 10.1016/j.freeradbiomed.2014.08.009
37. Markley MA Pierro A Eaton S Hepatocyte mitochondrial metabolism is inhibited in neonatal rat endotoxaemia: effects of glutamine Clin Sci 2002 102 3 337 344 10.1042/cs1020337
Markley MA, Pierro A, Eaton S. Hepatocyte mitochondrial metabolism is inhibited in neonatal rat endotoxaemia: effects of glutamine. Clin Sci. 2002;102(3):337–44.10.1042/cs1020337
38. Yao X Carlson D Sun Y Ma L Wolf SE Minei JP Zang QS Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model PLoS ONE 2015 10 10 e0139416 10.1371/journal.pone.0139416 26448624
Yao X, Carlson D, Sun Y, Ma L, Wolf SE, Minei JP, Zang QS. Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model. PLoS ONE. 2015;10(10):e0139416.26448624 10.1371/journal.pone.0139416
39. Crouser ED Julian MW Blaho DV Pfeiffer DR Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity Crit Care Med 2002 30 2 276 284 10.1097/00003246-200202000-00002 11889292
Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002;30(2):276–84.11889292 10.1097/00003246-200202000-00002
40. Escames G Lopez LC Tapias V Utrilla P Reiter RJ Hitos AB Leon J Rodriguez MI Acuna-Castroviejo D Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice J Pineal Res 2006 40 1 71 78 10.1111/j.1600-079X.2005.00281.x 16313501
Escames G, Lopez LC, Tapias V, Utrilla P, Reiter RJ, Hitos AB, Leon J, Rodriguez MI, Acuna-Castroviejo D. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J Pineal Res. 2006;40(1):71–8.16313501 10.1111/j.1600-079X.2005.00281.x
41. Nathan C Shiloh MU Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens Proc Natl Acad Sci USA 2000 97 16 8841 8848 10.1073/pnas.97.16.8841 10922044
Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA. 2000;97(16):8841–8.10922044 10.1073/pnas.97.16.8841
42. Garcia JA Ortiz F Miana J Doerrier C Fernandez-Ortiz M Rusanova I Escames G Garcia JJ Acuna-Castroviejo D Contribution of inducible and neuronal nitric oxide synthases to mitochondrial damage and melatonin rescue in LPS-treated mice J Physiol Biochem 2017 73 2 235 244 10.1007/s13105-017-0548-2 28110436
Garcia JA, Ortiz F, Miana J, Doerrier C, Fernandez-Ortiz M, Rusanova I, Escames G, Garcia JJ, Acuna-Castroviejo D. Contribution of inducible and neuronal nitric oxide synthases to mitochondrial damage and melatonin rescue in LPS-treated mice. J Physiol Biochem. 2017;73(2):235–44.28110436 10.1007/s13105-017-0548-2
43. Lopes-Pires ME Frade-Guanaes JO Quinlan GJ Clotting dysfunction in sepsis: a role for ROS and potential for therapeutic intervention Antioxidants (Basel) 2021 11 1 88 10.3390/antiox11010088 35052592
Lopes-Pires ME, Frade-Guanaes JO, Quinlan GJ. Clotting dysfunction in sepsis: a role for ROS and potential for therapeutic intervention. Antioxidants (Basel). 2021;11(1):88.35052592 10.3390/antiox11010088
44. Lee YM He W Liou YC The redox language in neurodegenerative diseases: oxidative post-translational modifications by hydrogen peroxide Cell Death Dis 2021 12 1 58 10.1038/s41419-020-03355-3 33431811
Lee YM, He W, Liou YC. The redox language in neurodegenerative diseases: oxidative post-translational modifications by hydrogen peroxide. Cell Death Dis. 2021;12(1):58.33431811 10.1038/s41419-020-03355-3
45. Zhao WY Zhang L Sui MX Zhu YH Zeng L Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury Sci Rep 2016 6 33201 10.1038/srep33201 27620507
Zhao WY, Zhang L, Sui MX, Zhu YH, Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury. Sci Rep. 2016;6:33201.27620507 10.1038/srep33201
46. Labiner HE Sas KM Baur JA Sims CA Sirt3 deletion increases inflammation and mortality in polymicrobial sepsis Surg Infect (Larchmt) 2023 24 9 788 796 10.1089/sur.2023.161 38015645
Labiner HE, Sas KM, Baur JA, Sims CA. Sirt3 deletion increases inflammation and mortality in polymicrobial sepsis. Surg Infect (Larchmt). 2023;24(9):788–96.38015645 10.1089/sur.2023.161
47. Sharma P Jha AB Dubey RS Pessarakli M Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions J Bot 2012 2012 217037
Sharma P, Jha AB, Dubey RS, Pessarakli M. Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions. J Bot. 2012;2012:217037.
48. Shiva S Brookes PS Patel RP Anderson PG Darley-Usmar VM Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase Proc Natl Acad Sci USA 2001 98 13 7212 7217 10.1073/pnas.131128898 11416204
Shiva S, Brookes PS, Patel RP, Anderson PG, Darley-Usmar VM. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc Natl Acad Sci USA. 2001;98(13):7212–7.11416204 10.1073/pnas.131128898
49. Brown GC Borutaite V Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols Biochim Biophys Acta 2004 1658 1–2 44 49 10.1016/j.bbabio.2004.03.016 15282173
Brown GC, Borutaite V. Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta. 2004;1658(1–2):44–9.15282173 10.1016/j.bbabio.2004.03.016
50. Brown GC Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase Biochim Biophys Acta 2001 1504 1 46 57 10.1016/S0005-2728(00)00238-3 11239484
Brown GC. Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta. 2001;1504(1):46–57.11239484 10.1016/S0005-2728(00)00238-3
51. Youle RJ Narendra DP Mechanisms of mitophagy Nat Rev Mol Cell Biol 2011 12 1 9 14 10.1038/nrm3028 21179058
Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12(1):9–14.21179058 10.1038/nrm3028
52. Li A Gao M Liu B Qin Y Chen L Liu H Wu H Gong G Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease Cell Death Dis 2022 13 5 444 10.1038/s41419-022-04906-6 35534453
Li A, Gao M, Liu B, Qin Y, Chen L, Liu H, Wu H, Gong G. Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease. Cell Death Dis. 2022;13(5):444.35534453 10.1038/s41419-022-04906-6
53. Yu J Nagasu H Murakami T Hoang H Broderick L Hoffman HM Horng T Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy Proc Natl Acad Sci USA 2014 111 43 15514 15519 10.1073/pnas.1414859111 25313054
Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci USA. 2014;111(43):15514–9.25313054 10.1073/pnas.1414859111
54. Patoli D Mignotte F Deckert V Dusuel A Dumont A Rieu A Jalil A Van Dongen K Bourgeois T Gautier T Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis J Clin Invest 2020 130 11 5858 5874 10.1172/JCI130996 32759503
Patoli D, Mignotte F, Deckert V, Dusuel A, Dumont A, Rieu A, Jalil A, Van Dongen K, Bourgeois T, Gautier T, et al. Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis. J Clin Invest. 2020;130(11):5858–74.32759503 10.1172/JCI130996
55. Dagvadorj J Mikulska-Ruminska K Tumurkhuu G Ratsimandresy RA Carriere J Andres AM Marek-Iannucci S Song Y Chen S Lane M Recruitment of pro-IL-1alpha to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation Proc Natl Acad Sci USA 2021 118 1 15 10.1073/pnas.2015632118
Dagvadorj J, Mikulska-Ruminska K, Tumurkhuu G, Ratsimandresy RA, Carriere J, Andres AM, Marek-Iannucci S, Song Y, Chen S, Lane M, et al. Recruitment of pro-IL-1alpha to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation. Proc Natl Acad Sci USA. 2021;118(1):15.10.1073/pnas.2015632118
56. Herzig S Shaw RJ AMPK: guardian of metabolism and mitochondrial homeostasis Nat Rev Mol Cell Biol 2018 19 2 121 135 10.1038/nrm.2017.95 28974774
Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121–35.28974774 10.1038/nrm.2017.95
57. Tadie JM Bae HB Deshane JS Bell CP Lazarowski ER Chaplin DD Thannickal VJ Abraham E Zmijewski JW Toll-like receptor 4 engagement inhibits adenosine 5'-monophosphate-activated protein kinase activation through a high mobility group box 1 protein-dependent mechanism Mol Med 2012 18 1 659 668 10.2119/molmed.2011.00401 22396017
Tadie JM, Bae HB, Deshane JS, Bell CP, Lazarowski ER, Chaplin DD, Thannickal VJ, Abraham E, Zmijewski JW. Toll-like receptor 4 engagement inhibits adenosine 5’-monophosphate-activated protein kinase activation through a high mobility group box 1 protein-dependent mechanism. Mol Med. 2012;18(1):659–68.22396017 10.2119/molmed.2011.00401
58. Ip WKE Hoshi N Shouval DS Snapper S Medzhitov R Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages Science 2017 356 6337 513 519 10.1126/science.aal3535 28473584
Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9.28473584 10.1126/science.aal3535
59. Zhong Z Umemura A Sanchez-Lopez E Liang S Shalapour S Wong J He F Boassa D Perkins G Ali SR NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria Cell 2016 164 5 896 910 10.1016/j.cell.2015.12.057 26919428
Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, et al. NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria. Cell. 2016;164(5):896–910.26919428 10.1016/j.cell.2015.12.057
60. Kim MJ Bae SH Ryu JC Kwon Y Oh JH Kwon J Moon JS Kim K Miyawaki A Lee MG SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages Autophagy 2016 12 8 1272 1291 10.1080/15548627.2016.1183081 27337507
Kim MJ, Bae SH, Ryu JC, Kwon Y, Oh JH, Kwon J, Moon JS, Kim K, Miyawaki A, Lee MG, et al. SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy. 2016;12(8):1272–91.27337507 10.1080/15548627.2016.1183081
61. Sun Y Yao X Zhang QJ Zhu M Liu ZP Ci B Xie Y Carlson D Rothermel BA Sun Y Beclin-1-dependent autophagy protects the heart during sepsis Circulation 2018 138 20 2247 2262 10.1161/CIRCULATIONAHA.117.032821 29853517
Sun Y, Yao X, Zhang QJ, Zhu M, Liu ZP, Ci B, Xie Y, Carlson D, Rothermel BA, Sun Y, et al. Beclin-1-dependent autophagy protects the heart during sepsis. Circulation. 2018;138(20):2247–62.29853517 10.1161/CIRCULATIONAHA.117.032821
62. Wang Y Zhu J Liu Z Shu S Fu Y Liu Y Cai J Tang C Liu Y Yin X The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury Redox Biol 2021 38 101767 10.1016/j.redox.2020.101767 33137712
Wang Y, Zhu J, Liu Z, Shu S, Fu Y, Liu Y, Cai J, Tang C, Liu Y, Yin X, et al. The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury. Redox Biol. 2021;38:101767.33137712 10.1016/j.redox.2020.101767
63. Crouser ED Julian MW Huff JE Struck J Cook CH Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis Crit Care Med 2006 34 9 2439 2446 10.1097/01.CCM.0000230240.02216.21 16791110
Crouser ED, Julian MW, Huff JE, Struck J, Cook CH. Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis. Crit Care Med. 2006;34(9):2439–46.16791110 10.1097/01.CCM.0000230240.02216.21
64. Sabouny R Shutt TE Reciprocal regulation of mitochondrial fission and fusion Trends Biochem Sci 2020 45 7 564 577 10.1016/j.tibs.2020.03.009 32291139
Sabouny R, Shutt TE. Reciprocal regulation of mitochondrial fission and fusion. Trends Biochem Sci. 2020;45(7):564–77.32291139 10.1016/j.tibs.2020.03.009
65. Held NM Houtkooper RH Mitochondrial quality control pathways as determinants of metabolic health BioEssays 2015 37 8 867 876 10.1002/bies.201500013 26010263
Held NM, Houtkooper RH. Mitochondrial quality control pathways as determinants of metabolic health. BioEssays. 2015;37(8):867–76.26010263 10.1002/bies.201500013
66. Tilokani L Nagashima S Paupe V Prudent J Mitochondrial dynamics: overview of molecular mechanisms Essays Biochem 2018 62 3 341 360 10.1042/EBC20170104 30030364
Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62(3):341–60.30030364 10.1042/EBC20170104
67. Zhang S Xu Y Zhu J Ma J Niu Q Wang X Carbon monoxide attenuates LPS-induced myocardial dysfunction in rats by regulating the mitochondrial dynamic equilibrium Eur J Pharmacol 2020 889 173726 10.1016/j.ejphar.2020.173726 33159931
Zhang S, Xu Y, Zhu J, Ma J, Niu Q, Wang X. Carbon monoxide attenuates LPS-induced myocardial dysfunction in rats by regulating the mitochondrial dynamic equilibrium. Eur J Pharmacol. 2020;889:173726.33159931 10.1016/j.ejphar.2020.173726
68. Gonzalez AS Elguero ME Finocchietto P Holod S Romorini L Miriuka SG Peralta JG Poderoso JJ Carreras MC Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis Free Radic Res 2014 48 7 769 783 10.3109/10715762.2014.906592 24720571
Gonzalez AS, Elguero ME, Finocchietto P, Holod S, Romorini L, Miriuka SG, Peralta JG, Poderoso JJ, Carreras MC. Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis. Free Radic Res. 2014;48(7):769–83.24720571 10.3109/10715762.2014.906592
69. Liu R Wang SC Li M Ma XH Jia XN Bu Y Sun L Yu KJ An inhibitor of DRP1 (Mdivi-1) alleviates LPS-induced septic AKI by inhibiting NLRP3 inflammasome activation Biomed Res Int 2020 2020 2398420 32733934
Liu R, Wang SC, Li M, Ma XH, Jia XN, Bu Y, Sun L, Yu KJ. An inhibitor of DRP1 (Mdivi-1) alleviates LPS-induced septic AKI by inhibiting NLRP3 inflammasome activation. Biomed Res Int. 2020;2020:2398420.32733934
70. Deng S Zhang L Mo Y Huang Y Li W Peng Q Huang L Ai Y Mdivi-1 attenuates lipopolysaccharide-induced acute lung injury by inhibiting MAPKs, oxidative stress and apoptosis Pulm Pharmacol Ther 2020 62 101918 10.1016/j.pupt.2020.101918 32251714
Deng S, Zhang L, Mo Y, Huang Y, Li W, Peng Q, Huang L, Ai Y. Mdivi-1 attenuates lipopolysaccharide-induced acute lung injury by inhibiting MAPKs, oxidative stress and apoptosis. Pulm Pharmacol Ther. 2020;62:101918.32251714 10.1016/j.pupt.2020.101918
71. Haileselassie B Mukherjee R Joshi AU Napier BA Massis LM Ostberg NP Queliconi BB Monack D Bernstein D Mochly-Rosen D Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy J Mol Cell Cardiol 2019 130 160 169 10.1016/j.yjmcc.2019.04.006 30981733
Haileselassie B, Mukherjee R, Joshi AU, Napier BA, Massis LM, Ostberg NP, Queliconi BB, Monack D, Bernstein D, Mochly-Rosen D. Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy. J Mol Cell Cardiol. 2019;130:160–9.30981733 10.1016/j.yjmcc.2019.04.006
72. Tan Y Ouyang H Xiao X Zhong J Dong M Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway Cell Stress Chaperones 2019 24 3 595 608 10.1007/s12192-019-00992-2 30993599
Tan Y, Ouyang H, Xiao X, Zhong J, Dong M. Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway. Cell Stress Chaperones. 2019;24(3):595–608.30993599 10.1007/s12192-019-00992-2
73. Norenberg MD Rao KV The mitochondrial permeability transition in neurologic disease Neurochem Int 2007 50 7–8 983 997 10.1016/j.neuint.2007.02.008 17397969
Norenberg MD, Rao KV. The mitochondrial permeability transition in neurologic disease. Neurochem Int. 2007;50(7–8):983–97.17397969 10.1016/j.neuint.2007.02.008
74. Westphal D Kluck RM Dewson G Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis Cell Death Differ 2014 21 2 196 205 10.1038/cdd.2013.139 24162660
Westphal D, Kluck RM, Dewson G. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ. 2014;21(2):196–205.24162660 10.1038/cdd.2013.139
75. McArthur K Whitehead LW Heddleston JM Li L Padman BS Oorschot V Geoghegan ND Chappaz S Davidson S San Chin H BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis Science 2018 359 6378 eaao6047 10.1126/science.aao6047 29472455
McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, Geoghegan ND, Chappaz S, Davidson S, San Chin H, et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018;359(6378):eaao6047.29472455 10.1126/science.aao6047
76. Riley JS Quarato G Cloix C Lopez J O'Prey J Pearson M Chapman J Sesaki H Carlin LM Passos JF Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis EMBO J 2018 37 17 e99238 10.15252/embj.201899238 30049712
Riley JS, Quarato G, Cloix C, Lopez J, O’Prey J, Pearson M, Chapman J, Sesaki H, Carlin LM, Passos JF, et al. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 2018;37(17):e99238.30049712 10.15252/embj.201899238
77. Elmore S Apoptosis: a review of programmed cell death Toxicol Pathol 2007 35 4 495 516 10.1080/01926230701320337 17562483
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.17562483 10.1080/01926230701320337
78. Li H Zhu H Xu CJ Yuan J Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis Cell 1998 94 4 491 501 10.1016/S0092-8674(00)81590-1 9727492
Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94(4):491–501.9727492 10.1016/S0092-8674(00)81590-1
79. Kuwana T Mackey MR Perkins G Ellisman MH Latterich M Schneiter R Green DR Newmeyer DD Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane Cell 2002 111 3 331 342 10.1016/S0092-8674(02)01036-X 12419244
Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 2002;111(3):331–42.12419244 10.1016/S0092-8674(02)01036-X
80. Desagher S Osen-Sand A Nichols A Eskes R Montessuit S Lauper S Maundrell K Antonsson B Martinou JC Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis J Cell Biol 1999 144 5 891 901 10.1083/jcb.144.5.891 10085289
Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol. 1999;144(5):891–901.10085289 10.1083/jcb.144.5.891
81. Chung CS Venet F Chen Y Jones LN Wilson DC Ayala CA Ayala A Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival Shock 2010 34 2 150 161 10.1097/SHK.0b013e3181cf70fb 20023601
Chung CS, Venet F, Chen Y, Jones LN, Wilson DC, Ayala CA, Ayala A. Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival. Shock. 2010;34(2):150–61.20023601 10.1097/SHK.0b013e3181cf70fb
82. Heilig R Dilucca M Boucher D Chen KW Hancz D Demarco B Shkarina K Broz P Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD Life Sci Alliance 2010 3 6 e202000735 10.26508/lsa.202000735
Heilig R, Dilucca M, Boucher D, Chen KW, Hancz D, Demarco B, Shkarina K, Broz P. Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD. Life Sci Alliance. 2020;3(6):e202000735.10.26508/lsa.202000735
83. Nakahira K Haspel JA Rathinam VA Lee SJ Dolinay T Lam HC Englert JA Rabinovitch M Cernadas M Kim HP Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome Nat Immunol 2011 12 3 222 230 10.1038/ni.1980 21151103
Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.21151103 10.1038/ni.1980
84. Larche J Lancel S Hassoun SM Favory R Decoster B Marchetti P Chopin C Neviere R Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality J Am Coll Cardiol 2006 48 2 377 385 10.1016/j.jacc.2006.02.069 16843190
Larche J, Lancel S, Hassoun SM, Favory R, Decoster B, Marchetti P, Chopin C, Neviere R. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol. 2006;48(2):377–85.16843190 10.1016/j.jacc.2006.02.069
85. Crouser ED Julian MW Joshi MS Bauer JA Wewers MD Hart JM Pfeiffer DR Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum during acute endotoxemia Crit Care Med 2002 30 12 2722 2728 10.1097/00003246-200212000-00017 12483064
Crouser ED, Julian MW, Joshi MS, Bauer JA, Wewers MD, Hart JM, Pfeiffer DR. Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum during acute endotoxemia. Crit Care Med. 2002;30(12):2722–8.12483064 10.1097/00003246-200212000-00017
86. Hu Y Yan JB Zheng MZ Song XH Wang LL Shen YL Chen YY Mitochondrial aldehyde dehydrogenase activity protects against lipopolysaccharide-induced cardiac dysfunction in rats Mol Med Rep 2015 11 2 1509 1515 10.3892/mmr.2014.2803 25351957
Hu Y, Yan JB, Zheng MZ, Song XH, Wang LL, Shen YL, Chen YY. Mitochondrial aldehyde dehydrogenase activity protects against lipopolysaccharide-induced cardiac dysfunction in rats. Mol Med Rep. 2015;11(2):1509–15.25351957 10.3892/mmr.2014.2803
87. Bernardi P Gerle C Halestrap AP Jonas EA Karch J Mnatsakanyan N Pavlov E Sheu S-S Soukas AA Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions Cell Death Differ 2023 30 8 1869 1885 10.1038/s41418-023-01187-0 37460667
Bernardi P, Gerle C, Halestrap AP, Jonas EA, Karch J, Mnatsakanyan N, Pavlov E, Sheu S-S, Soukas AA. Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions. Cell Death Differ. 2023;30(8):1869–85.37460667 10.1038/s41418-023-01187-0
88. Bonora M Giorgi C Pinton P Molecular mechanisms and consequences of mitochondrial permeability transition Nat Rev Mol Cell Biol 2022 23 4 266 285 10.1038/s41580-021-00433-y 34880425
Bonora M, Giorgi C, Pinton P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol. 2022;23(4):266–85.34880425 10.1038/s41580-021-00433-y
89. Orrenius S Gogvadze V Zhivotovsky B Mitochondrial oxidative stress: implications for cell death Annu Rev Pharmacol Toxicol 2007 47 143 183 10.1146/annurev.pharmtox.47.120505.105122 17029566
Orrenius S, Gogvadze V, Zhivotovsky B. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007;47:143–83.17029566 10.1146/annurev.pharmtox.47.120505.105122
90. Zorov DB Juhaszova M Sollott SJ Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release Physiol Rev 2014 94 3 909 950 10.1152/physrev.00026.2013 24987008
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94(3):909–50.24987008 10.1152/physrev.00026.2013
91. Wang S Moreau F Chadee K Gasdermins in innate host defense against entamoeba histolytica and other protozoan parasites Front Immunol 2022 13 900553 10.3389/fimmu.2022.900553 35795683
Wang S, Moreau F, Chadee K. Gasdermins in innate host defense against entamoeba histolytica and other protozoan parasites. Front Immunol. 2022;13:900553.35795683 10.3389/fimmu.2022.900553
92. Rogers C Erkes DA Nardone A Aplin AE Fernandes-Alnemri T Alnemri ES Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation Nat Commun 2019 10 1 1689 10.1038/s41467-019-09397-2 30976076
Rogers C, Erkes DA, Nardone A, Aplin AE, Fernandes-Alnemri T, Alnemri ES. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat Commun. 2019;10(1):1689.30976076 10.1038/s41467-019-09397-2
93. de Vasconcelos NM Van Opdenbosch N Van Gorp H Parthoens E Lamkanfi M Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture Cell Death Differ 2019 26 1 146 161 10.1038/s41418-018-0106-7 29666477
de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 2019;26(1):146–61.29666477 10.1038/s41418-018-0106-7
94. Huang LS Hong Z Wu W Xiong S Zhong M Gao X Rehman J Malik AB mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury Immunity 2020 52 3 475 486 e475 10.1016/j.immuni.2020.02.002 32164878
Huang LS, Hong Z, Wu W, Xiong S, Zhong M, Gao X, Rehman J, Malik AB. mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury. Immunity. 2020;52(3):475-486 e475.32164878 10.1016/j.immuni.2020.02.002
95. Miao R Jiang C Chang WY Zhang H An J Ho F Chen P Zhang H Junqueira C Amgalan D Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis Immunity 2023 56 11 2523 2541 e2528 10.1016/j.immuni.2023.10.004 37924812
Miao R, Jiang C, Chang WY, Zhang H, An J, Ho F, Chen P, Zhang H, Junqueira C, Amgalan D, et al. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis. Immunity. 2023;56(11):2523-2541 e2528.37924812 10.1016/j.immuni.2023.10.004
96. Lin PH Lin HY Kuo CC Yang LT N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting J Biomed Sci 2015 22 1 44 10.1186/s12929-015-0152-0 26100518
Lin PH, Lin HY, Kuo CC, Yang LT. N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting. J Biomed Sci. 2015;22(1):44.26100518 10.1186/s12929-015-0152-0
97. Kondolf HC D'Orlando DA Dubyak GR Abbott DW Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis J Biol Chem 2023 299 2 102908 10.1016/j.jbc.2023.102908 36642180
Kondolf HC, D’Orlando DA, Dubyak GR, Abbott DW. Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis. J Biol Chem. 2023;299(2):102908.36642180 10.1016/j.jbc.2023.102908
98. Takeuchi O Akira S Pattern recognition receptors and inflammation Cell 2010 140 6 805 820 10.1016/j.cell.2010.01.022 20303872
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.20303872 10.1016/j.cell.2010.01.022
99. Nong Y Wei X Yu D Inflammatory mechanisms and intervention strategies for sepsis-induced myocardial dysfunction Immun Inflamm Dis 2023 11 5 e860 10.1002/iid3.860 37249297
Nong Y, Wei X, Yu D. Inflammatory mechanisms and intervention strategies for sepsis-induced myocardial dysfunction. Immun Inflamm Dis. 2023;11(5):e860.37249297 10.1002/iid3.860
100. Abais JM Xia M Zhang Y Boini KM Li PL Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal 2015 22 13 1111 1129 10.1089/ars.2014.5994 25330206
Abais JM, Xia M, Zhang Y, Boini KM, Li PL. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22(13):1111–29.25330206 10.1089/ars.2014.5994
101. Zang QS Sadek H Maass DL Martinez B Ma L Kilgore JA Williams NS Frantz DE Wigginton JG Nwariaku FE Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model Am J Physiol Heart Circ Physiol 2012 302 9 H1847 1859 10.1152/ajpheart.00203.2011 22408027
Zang QS, Sadek H, Maass DL, Martinez B, Ma L, Kilgore JA, Williams NS, Frantz DE, Wigginton JG, Nwariaku FE, et al. Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model. Am J Physiol Heart Circ Physiol. 2012;302(9):H1847-1859.22408027 10.1152/ajpheart.00203.2011
102. Lowes DA Thottakam BM Webster NR Murphy MP Galley HF The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis Free Radic Biol Med 2008 45 11 1559 1565 10.1016/j.freeradbiomed.2008.09.003 18845241
Lowes DA, Thottakam BM, Webster NR, Murphy MP, Galley HF. The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med. 2008;45(11):1559–65.18845241 10.1016/j.freeradbiomed.2008.09.003
103. Xia Y Cao Y Sun Y Hong X Tang Y Yu J Hu H Ma W Qin K Bao R Calycosin alleviates sepsis-induced acute lung injury via the inhibition of mitochondrial ROS-mediated inflammasome activation Front Pharmacol 2021 12 690549 10.3389/fphar.2021.690549 34737695
Xia Y, Cao Y, Sun Y, Hong X, Tang Y, Yu J, Hu H, Ma W, Qin K, Bao R. Calycosin alleviates sepsis-induced acute lung injury via the inhibition of mitochondrial ROS-mediated inflammasome activation. Front Pharmacol. 2021;12:690549.34737695 10.3389/fphar.2021.690549
104. Zhou R Tardivel A Thorens B Choi I Tschopp J Thioredoxin-interacting protein links oxidative stress to inflammasome activation Nat Immunol 2010 11 2 136 140 10.1038/ni.1831 20023662
Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11(2):136–40.20023662 10.1038/ni.1831
105. Juliana C Fernandes-Alnemri T Kang S Farias A Qin F Alnemri ES Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation J Biol Chem 2012 287 43 36617 36622 10.1074/jbc.M112.407130 22948162
Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287(43):36617–22.22948162 10.1074/jbc.M112.407130
106. Bauernfeind F Bartok E Rieger A Franchi L Nunez G Hornung V Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome J Immunol 2011 187 2 613 617 10.4049/jimmunol.1100613 21677136
Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol. 2011;187(2):613–7.21677136 10.4049/jimmunol.1100613
107. Shimada K Crother TR Karlin J Dagvadorj J Chiba N Chen S Ramanujan VK Wolf AJ Vergnes L Ojcius DM Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis Immunity 2012 36 3 401 414 10.1016/j.immuni.2012.01.009 22342844
Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–14.22342844 10.1016/j.immuni.2012.01.009
108. Zhong Z Liang S Sanchez-Lopez E He F Shalapour S Lin XJ Wong J Ding S Seki E Schnabl B New mitochondrial DNA synthesis enables NLRP3 inflammasome activation Nature 2018 560 7717 198 203 10.1038/s41586-018-0372-z 30046112
Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, Wong J, Ding S, Seki E, Schnabl B, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560(7717):198–203.30046112 10.1038/s41586-018-0372-z
109. Xian H Watari K Sanchez-Lopez E Offenberger J Onyuru J Sampath H Ying W Hoffman HM Shadel GS Karin M Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling Immunity 2022 55 8 1370 1385 e1378 10.1016/j.immuni.2022.06.007 35835107
Xian H, Watari K, Sanchez-Lopez E, Offenberger J, Onyuru J, Sampath H, Ying W, Hoffman HM, Shadel GS, Karin M. Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity. 2022;55(8):1370-1385 e1378.35835107 10.1016/j.immuni.2022.06.007
110. Nozaki K Li L Miao EA Innate sensors trigger regulated cell death to combat intracellular infection Annu Rev Immunol 2022 40 469 498 10.1146/annurev-immunol-101320-011235 35138947
Nozaki K, Li L, Miao EA. Innate sensors trigger regulated cell death to combat intracellular infection. Annu Rev Immunol. 2022;40:469–98.35138947 10.1146/annurev-immunol-101320-011235
111. Li X Thome S Ma X Amrute-Nayak M Finigan A Kitt L Masters L James JR Shi Y Meng G MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism Nat Commun 2017 8 15986 10.1038/ncomms15986 28656979
Li X, Thome S, Ma X, Amrute-Nayak M, Finigan A, Kitt L, Masters L, James JR, Shi Y, Meng G, et al. MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nat Commun. 2017;8:15986.28656979 10.1038/ncomms15986
112. Zhou R Yazdi AS Menu P Tschopp J A role for mitochondria in NLRP3 inflammasome activation Nature 2011 469 7329 221 225 10.1038/nature09663 21124315
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5.21124315 10.1038/nature09663
113. Chen J Chen ZJ PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation Nature 2018 564 7734 71 76 10.1038/s41586-018-0761-3 30487600
Chen J, Chen ZJ. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature. 2018;564(7734):71–6.30487600 10.1038/s41586-018-0761-3
114. Magupalli VG Negro R Tian Y Hauenstein AV Di Caprio G Skillern W Deng Q Orning P Alam HB Maliga Z HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation Science 2020 369 6510 eaas8995 10.1126/science.aas8995 32943500
Magupalli VG, Negro R, Tian Y, Hauenstein AV, Di Caprio G, Skillern W, Deng Q, Orning P, Alam HB, Maliga Z, et al. HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science. 2020;369(6510):eaas8995.32943500 10.1126/science.aas8995
115. Pandey A Shen C Feng S Man SM Cell biology of inflammasome activation Trends Cell Biol 2021 31 11 924 939 10.1016/j.tcb.2021.06.010 34284921
Pandey A, Shen C, Feng S, Man SM. Cell biology of inflammasome activation. Trends Cell Biol. 2021;31(11):924–39.34284921 10.1016/j.tcb.2021.06.010
116. Misawa T Takahama M Kozaki T Lee H Zou J Saitoh T Akira S Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome Nat Immunol 2013 14 5 454 460 10.1038/ni.2550 23502856
Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14(5):454–60.23502856 10.1038/ni.2550
117. Subramanian N Natarajan K Clatworthy MR Wang Z Germain RN The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation Cell 2013 153 2 348 361 10.1016/j.cell.2013.02.054 23582325
Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell. 2013;153(2):348–61.23582325 10.1016/j.cell.2013.02.054
118. Iyer SS He Q Janczy JR Elliott EI Zhong Z Olivier AK Sadler JJ Knepper-Adrian V Han R Qiao L Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation Immunity 2013 39 2 311 323 10.1016/j.immuni.2013.08.001 23954133
Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity. 2013;39(2):311–23.23954133 10.1016/j.immuni.2013.08.001
119. Elliott EI Miller AN Banoth B Iyer SS Stotland A Weiss JP Gottlieb RA Sutterwala FS Cassel SL Cutting edge: mitochondrial assembly of the NLRP3 inflammasome complex is initiated at priming J Immunol 2018 200 9 3047 3052 10.4049/jimmunol.1701723 29602772
Elliott EI, Miller AN, Banoth B, Iyer SS, Stotland A, Weiss JP, Gottlieb RA, Sutterwala FS, Cassel SL. Cutting edge: mitochondrial assembly of the NLRP3 inflammasome complex is initiated at priming. J Immunol. 2018;200(9):3047–52.29602772 10.4049/jimmunol.1701723
120. Park S Juliana C Hong S Datta P Hwang I Fernandes-Alnemri T Yu JW Alnemri ES The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity J Immunol 2013 191 8 4358 4366 10.4049/jimmunol.1301170 24048902
Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, Yu JW, Alnemri ES. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol. 2013;191(8):4358–66.24048902 10.4049/jimmunol.1301170
121. Franchi L Eigenbrod T Munoz-Planillo R Ozkurede U Kim YG Arindam C Gale M Jr Silverman RH Colonna M Akira S Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux J Immunol 2014 193 8 4214 4222 10.4049/jimmunol.1400582 25225670
Franchi L, Eigenbrod T, Munoz-Planillo R, Ozkurede U, Kim YG, Arindam C, Gale M Jr, Silverman RH, Colonna M, Akira S, et al. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J Immunol. 2014;193(8):4214–22.25225670 10.4049/jimmunol.1400582
122. Ren Z Ding T Zuo Z Xu Z Deng J Wei Z Regulation of MAVS expression and signaling function in the antiviral innate immune response Front Immunol 2020 11 1030 10.3389/fimmu.2020.01030 32536927
Ren Z, Ding T, Zuo Z, Xu Z, Deng J, Wei Z. Regulation of MAVS expression and signaling function in the antiviral innate immune response. Front Immunol. 2020;11:1030.32536927 10.3389/fimmu.2020.01030
123. Andreeva L David L Rawson S Shen C Pasricha T Pelegrin P Wu H NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation Cell 2021 184 26 6299 6312 e6222 10.1016/j.cell.2021.11.011 34861190
Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, Wu H. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell. 2021;184(26):6299-6312 e6222.34861190 10.1016/j.cell.2021.11.011
124. Zhang Z Meszaros G He WT Xu Y de Fatima MH Mailly L Mihlan M Liu Y Puig Gamez M Goginashvili A Protein kinase D at the Golgi controls NLRP3 inflammasome activation J Exp Med 2017 214 9 2671 2693 10.1084/jem.20162040 28716882
Zhang Z, Meszaros G, He WT, Xu Y, de Fatima MH, Mailly L, Mihlan M, Liu Y, Puig Gamez M, Goginashvili A, et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J Exp Med. 2017;214(9):2671–93.28716882 10.1084/jem.20162040
125. Xiao L Magupalli VG Wu H Cryo-EM structures of the active NLRP3 inflammasome disc Nature 2023 613 7944 595 600 10.1038/s41586-022-05570-8 36442502
Xiao L, Magupalli VG, Wu H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature. 2023;613(7944):595–600.36442502 10.1038/s41586-022-05570-8
126. Fu J Wu H Structural mechanisms of NLRP3 inflammasome assembly and activation Annu Rev Immunol 2023 41 301 316 10.1146/annurev-immunol-081022-021207 36750315
Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol. 2023;41:301–16.36750315 10.1146/annurev-immunol-081022-021207
127. Ablasser A Chen ZJ cGAS in action: Expanding roles in immunity and inflammation Science 2019 363 6431 eaat8657 10.1126/science.aat8657 30846571
Ablasser A, Chen ZJ. cGAS in action: Expanding roles in immunity and inflammation. Science. 2019;363(6431):eaat8657.30846571 10.1126/science.aat8657
128. Xian H Karin M Oxidized mitochondrial DNA: a protective signal gone awry Trends Immunol 2023 44 3 188 200 10.1016/j.it.2023.01.006 36739208
Xian H, Karin M. Oxidized mitochondrial DNA: a protective signal gone awry. Trends Immunol. 2023;44(3):188–200.36739208 10.1016/j.it.2023.01.006
129. Gehrke N Mertens C Zillinger T Wenzel J Bald T Zahn S Tuting T Hartmann G Barchet W Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing Immunity 2013 39 3 482 495 10.1016/j.immuni.2013.08.004 23993650
Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, Tuting T, Hartmann G, Barchet W. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity. 2013;39(3):482–95.23993650 10.1016/j.immuni.2013.08.004
130. Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, Quintana C, Osorio JC, Wang Z, Zhao Y et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med 2013;10(12):e1001577; discussion e1001577.
131. Wang L Zhou W Wang K He S Chen Y Predictive value of circulating plasma mitochondrial DNA for Sepsis in the emergency department: observational study based on the Sepsis-3 definition BMC Emerg Med 2020 20 1 25 10.1186/s12873-020-00320-3 32299369
Wang L, Zhou W, Wang K, He S, Chen Y. Predictive value of circulating plasma mitochondrial DNA for Sepsis in the emergency department: observational study based on the Sepsis-3 definition. BMC Emerg Med. 2020;20(1):25.32299369 10.1186/s12873-020-00320-3
132. Schneck E Edinger F Hecker M Sommer N Pak O Weissmann N Hecker A Reichert M Markmann M Sander M Blood levels of free-circulating mitochondrial DNA in septic shock and postsurgical systemic inflammation and its influence on coagulation: a secondary analysis of a prospective observational study J Clin Med 2020 9 7 2056 10.3390/jcm9072056 32629885
Schneck E, Edinger F, Hecker M, Sommer N, Pak O, Weissmann N, Hecker A, Reichert M, Markmann M, Sander M, et al. Blood levels of free-circulating mitochondrial DNA in septic shock and postsurgical systemic inflammation and its influence on coagulation: a secondary analysis of a prospective observational study. J Clin Med. 2020;9(7):2056.32629885 10.3390/jcm9072056
133. Liu Q Wu J Zhang X Li X Wu X Zhao Y Ren J Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury Cell Death Dis 2021 12 7 673 10.1038/s41419-021-03961-9 34218252
Liu Q, Wu J, Zhang X, Li X, Wu X, Zhao Y, Ren J. Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury. Cell Death Dis. 2021;12(7):673.34218252 10.1038/s41419-021-03961-9
134. Hu Q Ren H Li G Wang D Zhou Q Wu J Zheng J Huang J Slade DA Wu X STING-mediated intestinal barrier dysfunction contributes to lethal sepsis EBioMedicine 2019 41 497 508 10.1016/j.ebiom.2019.02.055 30878597
Hu Q, Ren H, Li G, Wang D, Zhou Q, Wu J, Zheng J, Huang J, Slade DA, Wu X, et al. STING-mediated intestinal barrier dysfunction contributes to lethal sepsis. EBioMedicine. 2019;41:497–508.30878597 10.1016/j.ebiom.2019.02.055
135. Xu L Li M Yang Y Zhang C Xie Z Tang J Shi Z Chen S Li G Gu Y Salmonella induces the cGAS-STING-dependent type I interferon response in murine macrophages by triggering mtDNA release MBio 2022 13 3 e0363221 10.1128/mbio.03632-21 35604097
Xu L, Li M, Yang Y, Zhang C, Xie Z, Tang J, Shi Z, Chen S, Li G, Gu Y, et al. Salmonella induces the cGAS-STING-dependent type I interferon response in murine macrophages by triggering mtDNA release. MBio. 2022;13(3):e0363221.35604097 10.1128/mbio.03632-21
136. Zhang RX Kang R Tang DL STING1 in sepsis: mechanisms, functions, and implications Chin J Traumatol 2022 25 1 1 10 10.1016/j.cjtee.2021.07.009 34334261
Zhang RX, Kang R, Tang DL. STING1 in sepsis: mechanisms, functions, and implications. Chin J Traumatol. 2022;25(1):1–10.34334261 10.1016/j.cjtee.2021.07.009
137. Hemmi H Takeuchi O Kawai T Kaisho T Sato S Sanjo H Matsumoto M Hoshino K Wagner H Takeda K A Toll-like receptor recognizes bacterial DNA Nature 2000 408 6813 740 745 10.1038/35047123 11130078
Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–5.11130078 10.1038/35047123
138. Lund J Sato A Akira S Medzhitov R Iwasaki A Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells J Exp Med 2003 198 3 513 520 10.1084/jem.20030162 12900525
Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003;198(3):513–20.12900525 10.1084/jem.20030162
139. Zhang Q Raoof M Chen Y Sumi Y Sursal T Junger W Brohi K Itagaki K Hauser CJ Circulating mitochondrial DAMPs cause inflammatory responses to injury Nature 2010 464 7285 104 107 10.1038/nature08780 20203610
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.20203610 10.1038/nature08780
140. Tsuji N Tsuji T Ohashi N Kato A Fujigaki Y Yasuda H Role of Mitochondrial DNA in septic AKI via toll-like receptor 9 J Am Soc Nephrol 2016 27 7 2009 2020 10.1681/ASN.2015040376 26574043
Tsuji N, Tsuji T, Ohashi N, Kato A, Fujigaki Y, Yasuda H. Role of Mitochondrial DNA in septic AKI via toll-like receptor 9. J Am Soc Nephrol. 2016;27(7):2009–20.26574043 10.1681/ASN.2015040376
141. Yasuda H Leelahavanichkul A Tsunoda S Dear JW Takahashi Y Ito S Hu X Zhou H Doi K Childs R Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury Am J Physiol Renal Physiol 2008 294 5 F1050 F1058 10.1152/ajprenal.00461.2007 18305095
Yasuda H, Leelahavanichkul A, Tsunoda S, Dear JW, Takahashi Y, Ito S, Hu X, Zhou H, Doi K, Childs R, et al. Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am J Physiol Renal Physiol. 2008;294(5):F1050–8.18305095 10.1152/ajprenal.00461.2007
142. Plitas G Burt BM Nguyen HM Bamboat ZM DeMatteo RP Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis J Exp Med 2008 205 6 1277 1283 10.1084/jem.20080162 18474631
Plitas G, Burt BM, Nguyen HM, Bamboat ZM, DeMatteo RP. Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis. J Exp Med. 2008;205(6):1277–83.18474631 10.1084/jem.20080162
143. Liu J Zhou G Wang X Liu D Metabolic reprogramming consequences of sepsis: adaptations and contradictions Cell Mol Life Sci 2022 79 8 456 10.1007/s00018-022-04490-0 35904600
Liu J, Zhou G, Wang X, Liu D. Metabolic reprogramming consequences of sepsis: adaptations and contradictions. Cell Mol Life Sci. 2022;79(8):456.35904600 10.1007/s00018-022-04490-0
144. Liu C Wei W Huang Y Fu P Zhang L Zhao Y Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications Metabolism 2024 158 155974 10.1016/j.metabol.2024.155974 38996912
Liu C, Wei W, Huang Y, Fu P, Zhang L, Zhao Y. Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications. Metabolism. 2024;158:155974.38996912 10.1016/j.metabol.2024.155974
145. Van Wyngene L Vandewalle J Libert C Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? EMBO Mol Med 2018 10 8 e8712 10.15252/emmm.201708712 29976786
Van Wyngene L, Vandewalle J, Libert C. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? EMBO Mol Med. 2018;10(8):e8712.29976786 10.15252/emmm.201708712
146. Pan T Sun S Chen Y Tian R Chen E Tan R Wang X Liu Z Liu J Qu H Immune effects of PI3K/Akt/HIF-1alpha-regulated glycolysis in polymorphonuclear neutrophils during sepsis Crit Care 2022 26 1 29 10.1186/s13054-022-03893-6 35090526
Pan T, Sun S, Chen Y, Tian R, Chen E, Tan R, Wang X, Liu Z, Liu J, Qu H. Immune effects of PI3K/Akt/HIF-1alpha-regulated glycolysis in polymorphonuclear neutrophils during sepsis. Crit Care. 2022;26(1):29.35090526 10.1186/s13054-022-03893-6
147. Tan C Gu J Chen H Li T Deng H Liu K Liu M Tan S Xiao Z Zhang H Inhibition of aerobic glycolysis promotes neutrophil to influx to the infectious site via CXCR2 in sepsis Shock 2020 53 1 114 123 10.1097/SHK.0000000000001334 30829852
Tan C, Gu J, Chen H, Li T, Deng H, Liu K, Liu M, Tan S, Xiao Z, Zhang H, et al. Inhibition of aerobic glycolysis promotes neutrophil to influx to the infectious site via CXCR2 in sepsis. Shock. 2020;53(1):114–23.30829852 10.1097/SHK.0000000000001334
148. Hotchkiss RS Swanson PE Freeman BD Tinsley KW Cobb JP Matuschak GM Buchman TG Karl IE Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction Crit Care Med 1999 27 7 1230 1251 10.1097/00003246-199907000-00002 10446814
Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–51.10446814 10.1097/00003246-199907000-00002
149. Singer M De Santis V Vitale D Jeffcoate W Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation Lancet 2004 364 9433 545 548 10.1016/S0140-6736(04)16815-3 15302200
Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364(9433):545–8.15302200 10.1016/S0140-6736(04)16815-3
150. Brealey D Brand M Hargreaves I Heales S Land J Smolenski R Davies NA Cooper CE Singer M Association between mitochondrial dysfunction and severity and outcome of septic shock Lancet 2002 360 9328 219 223 10.1016/S0140-6736(02)09459-X 12133657
Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360(9328):219–23.12133657 10.1016/S0140-6736(02)09459-X
151. Dhanasekaran A Kotamraju S Kalivendi SV Matsunaga T Shang T Keszler A Joseph J Kalyanaraman B Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis J Biol Chem 2004 279 36 37575 37587 10.1074/jbc.M404003200 15220329
Dhanasekaran A, Kotamraju S, Kalivendi SV, Matsunaga T, Shang T, Keszler A, Joseph J, Kalyanaraman B. Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem. 2004;279(36):37575–87.15220329 10.1074/jbc.M404003200
152. McCormick B Lowes DA Colvin L Torsney C Galley HF MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model Br J Anaesth 2016 117 5 659 666 10.1093/bja/aew309 27799181
McCormick B, Lowes DA, Colvin L, Torsney C, Galley HF. MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model. Br J Anaesth. 2016;117(5):659–66.27799181 10.1093/bja/aew309
153. Gioscia-Ryan RA LaRocca TJ Sindler AL Zigler MC Murphy MP Seals DR Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice J Physiol 2014 592 12 2549 2561 10.1113/jphysiol.2013.268680 24665093
Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol. 2014;592(12):2549–61.24665093 10.1113/jphysiol.2013.268680
154. Kalyanaraman B Cheng G Hardy M You M OXPHOS-targeting drugs in oncology: new perspectives Expert Opin Ther Targets 2023 27 10 939 952 10.1080/14728222.2023.2261631 37736880
Kalyanaraman B, Cheng G, Hardy M, You M. OXPHOS-targeting drugs in oncology: new perspectives. Expert Opin Ther Targets. 2023;27(10):939–52.37736880 10.1080/14728222.2023.2261631
155. Zhang S Zhou Q Li Y Zhang Y Wu Y MitoQ modulates lipopolysaccharide-induced intestinal barrier dysfunction via regulating Nrf2 signaling Mediat Inflamm 2020 2020 3276148 10.1155/2020/3276148
Zhang S, Zhou Q, Li Y, Zhang Y, Wu Y. MitoQ modulates lipopolysaccharide-induced intestinal barrier dysfunction via regulating Nrf2 signaling. Mediat Inflamm. 2020;2020:3276148.10.1155/2020/3276148
156. Supinski GS Murphy MP Callahan LA MitoQ administration prevents endotoxin-induced cardiac dysfunction Am J Physiol Regul Integr Comp Physiol 2009 297 4 R1095 1102 10.1152/ajpregu.90902.2008 19657095
Supinski GS, Murphy MP, Callahan LA. MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 2009;297(4):R1095-1102.19657095 10.1152/ajpregu.90902.2008
157. Supinski GS Schroder EA Wang L Morris AJ Callahan LAP Mitoquinone mesylate (MitoQ) prevents sepsis-induced diaphragm dysfunction J Appl Physiol (1985) 2021 131 2 778 787 10.1152/japplphysiol.01053.2020 34197233
Supinski GS, Schroder EA, Wang L, Morris AJ, Callahan LAP. Mitoquinone mesylate (MitoQ) prevents sepsis-induced diaphragm dysfunction. J Appl Physiol (1985). 2021;131(2):778–87.34197233 10.1152/japplphysiol.01053.2020
158. Smith RA Porteous CM Coulter CV Murphy MP Selective targeting of an antioxidant to mitochondria Eur J Biochem 1999 263 3 709 716 10.1046/j.1432-1327.1999.00543.x 10469134
Smith RA, Porteous CM, Coulter CV, Murphy MP. Selective targeting of an antioxidant to mitochondria. Eur J Biochem. 1999;263(3):709–16.10469134 10.1046/j.1432-1327.1999.00543.x
159. Lowes DA Webster NR Murphy MP Galley HF Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis Br J Anaesth 2013 110 3 472 480 10.1093/bja/aes577 23381720
Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth. 2013;110(3):472–80.23381720 10.1093/bja/aes577
160. Trnka J Blaikie FH Smith RA Murphy MP A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria Free Radic Biol Med 2008 44 7 1406 1419 10.1016/j.freeradbiomed.2007.12.036 18206669
Trnka J, Blaikie FH, Smith RA, Murphy MP. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic Biol Med. 2008;44(7):1406–19.18206669 10.1016/j.freeradbiomed.2007.12.036
161. Arulkumaran N Pollen SJ Tidswell R Gaupp C Peters VBM Stanzani G Snow TAC Duchen MR Singer M Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats Br J Anaesth 2021 127 4 577 586 10.1016/j.bja.2021.05.036 34332740
Arulkumaran N, Pollen SJ, Tidswell R, Gaupp C, Peters VBM, Stanzani G, Snow TAC, Duchen MR, Singer M. Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats. Br J Anaesth. 2021;127(4):577–86.34332740 10.1016/j.bja.2021.05.036
162. Navas LE Carnero A NAD(+) metabolism, stemness, the immune response, and cancer Signal Transduct Target Ther 2021 6 1 2 10.1038/s41392-020-00354-w 33384409
Navas LE, Carnero A. NAD(+) metabolism, stemness, the immune response, and cancer. Signal Transduct Target Ther. 2021;6(1):2.33384409 10.1038/s41392-020-00354-w
163. Liaudet L Mabley JG Soriano FG Pacher P Marton A Hasko G Szabo C Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture Am J Respir Crit Care Med 2001 164 7 1213 1220 10.1164/ajrccm.164.7.2101013 11673212
Liaudet L, Mabley JG, Soriano FG, Pacher P, Marton A, Hasko G, Szabo C. Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. Am J Respir Crit Care Med. 2001;164(7):1213–20.11673212 10.1164/ajrccm.164.7.2101013
164. Cao T Ni R Ding W Ji X Fan GC Zhang Z Peng T Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis J Transl Med 2023 21 1 883 10.1186/s12967-023-04767-3 38057866
Cao T, Ni R, Ding W, Ji X, Fan GC, Zhang Z, Peng T. Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis. J Transl Med. 2023;21(1):883.38057866 10.1186/s12967-023-04767-3
165. Hong G Zheng D Zhang L Ni R Wang G Fan GC Lu Z Peng T Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis Free Radic Biol Med 2018 123 125 137 10.1016/j.freeradbiomed.2018.05.073 29803807
Hong G, Zheng D, Zhang L, Ni R, Wang G, Fan GC, Lu Z, Peng T. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis. Free Radic Biol Med. 2018;123:125–37.29803807 10.1016/j.freeradbiomed.2018.05.073
166. Ye M Zhao Y Wang Y Xie R Tong Y Sauer JD Gong S NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis Nat Nanotechnol 2022 17 8 880 890 10.1038/s41565-022-01137-w 35668170
Ye M, Zhao Y, Wang Y, Xie R, Tong Y, Sauer JD, Gong S. NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis. Nat Nanotechnol. 2022;17(8):880–90.35668170 10.1038/s41565-022-01137-w
167. Ryu D Mouchiroud L Andreux PA Katsyuba E Moullan N Nicolet-Dit-Felix AA Williams EG Jha P Lo Sasso G Huzard D Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents Nat Med 2016 22 8 879 888 10.1038/nm.4132 27400265
Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Felix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879–88.27400265 10.1038/nm.4132
168. Yang Y Hu Q Kang H Li J Zhao X Zhu L Tang W Wan M Urolithin A protects severe acute pancreatitis-associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes MedComm (2020) 2023 4 6 e459 38116065
Yang Y, Hu Q, Kang H, Li J, Zhao X, Zhu L, Tang W, Wan M. Urolithin A protects severe acute pancreatitis-associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes. MedComm (2020). 2023;4(6):e459.38116065
169. Abdelazeem KNM Kalo MZ Beer-Hammer S Lang F The gut microbiota metabolite urolithin A inhibits NF-kappaB activation in LPS stimulated BMDMs Sci Rep 2021 11 1 7117 10.1038/s41598-021-86514-6 33782464
Abdelazeem KNM, Kalo MZ, Beer-Hammer S, Lang F. The gut microbiota metabolite urolithin A inhibits NF-kappaB activation in LPS stimulated BMDMs. Sci Rep. 2021;11(1):7117.33782464 10.1038/s41598-021-86514-6
170. Liu S D'Amico D Shankland E Bhayana S Garcia JM Aebischer P Rinsch C Singh A Marcinek DJ Effect of urolithin a supplementation on muscle endurance and mitochondrial health in older adults: a randomized clinical trial JAMA Netw Open 2022 5 1 e2144279 10.1001/jamanetworkopen.2021.44279 35050355
Liu S, D’Amico D, Shankland E, Bhayana S, Garcia JM, Aebischer P, Rinsch C, Singh A, Marcinek DJ. Effect of urolithin a supplementation on muscle endurance and mitochondrial health in older adults: a randomized clinical trial. JAMA Netw Open. 2022;5(1):e2144279.35050355 10.1001/jamanetworkopen.2021.44279
171. Andreux PA Blanco-Bose W Ryu D Burdet F Ibberson M Aebischer P Auwerx J Singh A Rinsch C The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans Nat Metab 2019 1 6 595 603 10.1038/s42255-019-0073-4 32694802
Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019;1(6):595–603.32694802 10.1038/s42255-019-0073-4
172. Zhu P Chen Y Wang J Lin G Wang R Que Y Zhou J Xu G Luo J Du Y Receptor-interacting protein kinase 3 suppresses mitophagy activation via the yes-associated protein/transcription factor EB pathways in septic cardiomyopathy Front Cardiovasc Med 2022 9 856041 10.3389/fcvm.2022.856041 35402535
Zhu P, Chen Y, Wang J, Lin G, Wang R, Que Y, Zhou J, Xu G, Luo J, Du Y. Receptor-interacting protein kinase 3 suppresses mitophagy activation via the yes-associated protein/transcription factor EB pathways in septic cardiomyopathy. Front Cardiovasc Med. 2022;9:856041.35402535 10.3389/fcvm.2022.856041
173. Wang Y Jasper H Toan S Muid D Chang X Zhou H Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury Redox Biol 2021 45 102049 10.1016/j.redox.2021.102049 34174558
Wang Y, Jasper H, Toan S, Muid D, Chang X, Zhou H. Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury. Redox Biol. 2021;45:102049.34174558 10.1016/j.redox.2021.102049
174. Jiao P Wang Y Ren G Chu D Li Y Yang Y Sang T Urolithin A exerts a protective effect on lipopolysaccharide-induced acute lung injury by regulating HMGB1-mediated MAPK and NF-kappaB signaling pathways Naunyn Schmiedebergs Arch Pharmacol 2024 397 8 5765 5777 10.1007/s00210-024-02977-0 38319388
Jiao P, Wang Y, Ren G, Chu D, Li Y, Yang Y, Sang T. Urolithin A exerts a protective effect on lipopolysaccharide-induced acute lung injury by regulating HMGB1-mediated MAPK and NF-kappaB signaling pathways. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(8):5765–77.38319388 10.1007/s00210-024-02977-0
175. Libert C Ayala A Bauer M Cavaillon JM Deutschman C Frostell C Knapp S Kozlov AV Wang P Osuchowski MF Part II: minimum quality threshold in preclinical sepsis studies (MQTiPSS) for types of infections and organ dysfunction endpoints Shock 2019 51 1 23 32 10.1097/SHK.0000000000001242 30106873
Libert C, Ayala A, Bauer M, Cavaillon JM, Deutschman C, Frostell C, Knapp S, Kozlov AV, Wang P, Osuchowski MF, et al. Part II: minimum quality threshold in preclinical sepsis studies (MQTiPSS) for types of infections and organ dysfunction endpoints. Shock. 2019;51(1):23–32.30106873 10.1097/SHK.0000000000001242
176. Joffre J Hellman J Ince C Ait-Oufella H Endothelial responses in sepsis Am J Respir Crit Care Med 2020 202 3 361 370 10.1164/rccm.201910-1911TR 32101446
Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial responses in sepsis. Am J Respir Crit Care Med. 2020;202(3):361–70.32101446 10.1164/rccm.201910-1911TR
177. Cassidy-Stone A Chipuk JE Ingerman E Song C Yoo C Kuwana T Kurth MJ Shaw JT Hinshaw JE Green DR Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization Dev Cell 2008 14 2 193 204 10.1016/j.devcel.2007.11.019 18267088
Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14(2):193–204.18267088 10.1016/j.devcel.2007.11.019
178. Manczak M Kandimalla R Yin X Reddy PH Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity Hum Mol Genet 2019 28 2 177 199 10.1093/hmg/ddy335 30239719
Manczak M, Kandimalla R, Yin X, Reddy PH. Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity. Hum Mol Genet. 2019;28(2):177–99.30239719 10.1093/hmg/ddy335
179. Zhang Q Liu Z Huang X Heng X Wu J Chen Z Guo X Fan J Huang Q Mdivi-1 alleviates sepsis-induced liver injury by inhibiting sting signaling activation Shock 2024 62 1 95 102 10.1097/SHK.0000000000002349 38526162
Zhang Q, Liu Z, Huang X, Heng X, Wu J, Chen Z, Guo X, Fan J, Huang Q. Mdivi-1 alleviates sepsis-induced liver injury by inhibiting sting signaling activation. Shock. 2024;62(1):95–102.38526162 10.1097/SHK.0000000000002349
180. Fu Q Zhang YB Shi CX Jiang M Lu K Fu ZH Ruan JP Wu J Gu XP GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy J Neuroinflamm 2024 21 1 96 10.1186/s12974-024-03084-w
Fu Q, Zhang YB, Shi CX, Jiang M, Lu K, Fu ZH, Ruan JP, Wu J, Gu XP. GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy. J Neuroinflamm. 2024;21(1):96.10.1186/s12974-024-03084-w
181. Haileselassie B Joshi AU Minhas PS Mukherjee R Andreasson KI Mochly-Rosen D Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy J Neuroinflammation 2020 17 1 36 10.1186/s12974-019-1689-8 31987040
Haileselassie B, Joshi AU, Minhas PS, Mukherjee R, Andreasson KI, Mochly-Rosen D. Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy. J Neuroinflammation. 2020;17(1):36.31987040 10.1186/s12974-019-1689-8
182. de Paiva CS Pflugfelder SC Ng SM Akpek EK Topical cyclosporine A therapy for dry eye syndrome Cochrane Database Syst Rev 2019 9 9 CD010051 31517988
de Paiva CS, Pflugfelder SC, Ng SM, Akpek EK. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst Rev. 2019;9(9):CD010051.31517988
183. Molnar AO Fergusson D Tsampalieros AK Bennett A Fergusson N Ramsay T Knoll GA Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis BMJ 2015 350 h3163 10.1136/bmj.h3163 26101226
Molnar AO, Fergusson D, Tsampalieros AK, Bennett A, Fergusson N, Ramsay T, Knoll GA. Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ. 2015;350:h3163.26101226 10.1136/bmj.h3163
184. Luna-Sanchez M Bianchi P Quintana A Mitochondria-induced immune response as a trigger for neurodegeneration: a pathogen from within Int J Mol Sci 2021 22 16 8523 10.3390/ijms22168523 34445229
Luna-Sanchez M, Bianchi P, Quintana A. Mitochondria-induced immune response as a trigger for neurodegeneration: a pathogen from within. Int J Mol Sci. 2021;22(16):8523.34445229 10.3390/ijms22168523
185. Liddicoat AM Lavelle EC Modulation of innate immunity by cyclosporine A Biochem Pharmacol 2019 163 472 480 10.1016/j.bcp.2019.03.022 30880061
Liddicoat AM, Lavelle EC. Modulation of innate immunity by cyclosporine A. Biochem Pharmacol. 2019;163:472–80.30880061 10.1016/j.bcp.2019.03.022
186. Xiao Z Jia B Zhao X Bi S Meng W Attenuation of lipopolysaccharide-induced acute lung injury by cyclosporine-A via suppression of mitochondrial DNA Med Sci Monit 2018 24 7682 7688 10.12659/MSM.909909 30367813
Xiao Z, Jia B, Zhao X, Bi S, Meng W. Attenuation of lipopolysaccharide-induced acute lung injury by cyclosporine-A via suppression of mitochondrial DNA. Med Sci Monit. 2018;24:7682–8.30367813 10.12659/MSM.909909
187. Fauvel H Marchetti P Obert G Joulain O Chopin C Formstecher P Neviere R Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats Am J Respir Crit Care Med 2002 165 4 449 455 10.1164/ajrccm.165.4.2105084 11850335
Fauvel H, Marchetti P, Obert G, Joulain O, Chopin C, Formstecher P, Neviere R. Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats. Am J Respir Crit Care Med. 2002;165(4):449–55.11850335 10.1164/ajrccm.165.4.2105084
188. Joshi MS Julian MW Huff JE Bauer JA Xia Y Crouser ED Calcineurin regulates myocardial function during acute endotoxemia Am J Respir Crit Care Med 2006 173 9 999 1007 10.1164/rccm.200411-1507OC 16424445
Joshi MS, Julian MW, Huff JE, Bauer JA, Xia Y, Crouser ED. Calcineurin regulates myocardial function during acute endotoxemia. Am J Respir Crit Care Med. 2006;173(9):999–1007.16424445 10.1164/rccm.200411-1507OC
189. Flory J Lipska K Metformin in 2019 JAMA 2019 321 19 1926 1927 10.1001/jama.2019.3805 31009043
Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321(19):1926–7.31009043 10.1001/jama.2019.3805
190. Lv Z Guo Y Metformin and its benefits for various diseases Front Endocrinol (Lausanne) 2020 11 191 10.3389/fendo.2020.00191 32425881
Lv Z, Guo Y. Metformin and its benefits for various diseases. Front Endocrinol (Lausanne). 2020;11:191.32425881 10.3389/fendo.2020.00191
191. Liu Z Bone N Jiang S Park DW Tadie JM Deshane J Rodriguez CA Pittet JF Abraham E Zmijewski JW AMP-activated protein kinase and glycogen synthase kinase 3beta modulate the severity of sepsis-induced lung injury Mol Med 2016 21 1 937 950 10.2119/molmed.2015.00198 26650187
Liu Z, Bone N, Jiang S, Park DW, Tadie JM, Deshane J, Rodriguez CA, Pittet JF, Abraham E, Zmijewski JW. AMP-activated protein kinase and glycogen synthase kinase 3beta modulate the severity of sepsis-induced lung injury. Mol Med. 2016;21(1):937–50.26650187 10.2119/molmed.2015.00198
192. Fan SY Zhao ZC Liu XL Peng YG Zhu HM Yan SF Liu YJ Xie Q Jiang Y Zeng SZ Metformin mitigates sepsis-induced acute lung injury and inflammation in young mice by suppressing the S100A8/A9-NLRP3-IL-1beta signaling pathway J Inflamm Res 2024 17 3785 3799 10.2147/JIR.S460413 38895139
Fan SY, Zhao ZC, Liu XL, Peng YG, Zhu HM, Yan SF, Liu YJ, Xie Q, Jiang Y, Zeng SZ. Metformin mitigates sepsis-induced acute lung injury and inflammation in young mice by suppressing the S100A8/A9-NLRP3-IL-1beta signaling pathway. J Inflamm Res. 2024;17:3785–99.38895139 10.2147/JIR.S460413
193. Tang G Yang H Chen J Shi M Ge L Ge X Zhu G Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway Oncotarget 2017 8 58 97977 97989 10.18632/oncotarget.20105 29228667
Tang G, Yang H, Chen J, Shi M, Ge L, Ge X, Zhu G. Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget. 2017;8(58):97977–89.29228667 10.18632/oncotarget.20105
194. Liang H Song H Zhang X Song G Wang Y Ding X Duan X Li L Sun T Kan Q Metformin attenuated sepsis-related liver injury by modulating gut microbiota Emerg Microbes Infect 2022 11 1 815 828 10.1080/22221751.2022.2045876 35191819
Liang H, Song H, Zhang X, Song G, Wang Y, Ding X, Duan X, Li L, Sun T, Kan Q. Metformin attenuated sepsis-related liver injury by modulating gut microbiota. Emerg Microbes Infect. 2022;11(1):815–28.35191819 10.1080/22221751.2022.2045876
195. Doenyas-Barak K Beberashvili I Marcus R Efrati S Lactic acidosis and severe septic shock in metformin users: a cohort study Crit Care 2016 20 10 10.1186/s13054-015-1180-6 26775158
Doenyas-Barak K, Beberashvili I, Marcus R, Efrati S. Lactic acidosis and severe septic shock in metformin users: a cohort study. Crit Care. 2016;20:10.26775158 10.1186/s13054-015-1180-6
196. Green JP Berger T Garg N Suarez A Hagar Y Radeos MS Panacek EA Impact of metformin use on the prognostic value of lactate in sepsis Am J Emerg Med 2012 30 9 1667 1673 10.1016/j.ajem.2012.01.014 22424991
Green JP, Berger T, Garg N, Suarez A, Hagar Y, Radeos MS, Panacek EA. Impact of metformin use on the prognostic value of lactate in sepsis. Am J Emerg Med. 2012;30(9):1667–73.22424991 10.1016/j.ajem.2012.01.014
197. Jochmans S Alphonsine JE Chelly J Vong LVP Sy O Rolin N Ellrodt O Monchi M Vinsonneau C Does metformin exposure before ICU stay have any impact on patients' outcome? A retrospective cohort study of diabetic patients Ann Intensive Care 2017 7 1 116 10.1186/s13613-017-0336-8 29198069
Jochmans S, Alphonsine JE, Chelly J, Vong LVP, Sy O, Rolin N, Ellrodt O, Monchi M, Vinsonneau C. Does metformin exposure before ICU stay have any impact on patients’ outcome? A retrospective cohort study of diabetic patients. Ann Intensive Care. 2017;7(1):116.29198069 10.1186/s13613-017-0336-8
198. van Vught LA Scicluna BP Hoogendijk AJ Wiewel MA Klein Klouwenberg PM Cremer OL Horn J Nurnberg P Bonten MM Schultz MJ Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients Crit Care 2016 20 1 252 10.1186/s13054-016-1429-8 27495247
van Vught LA, Scicluna BP, Hoogendijk AJ, Wiewel MA, Klein Klouwenberg PM, Cremer OL, Horn J, Nurnberg P, Bonten MM, Schultz MJ, et al. Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients. Crit Care. 2016;20(1):252.27495247 10.1186/s13054-016-1429-8
199. Park J Hwang SY Jo IJ Jeon K Suh GY Lee TR Yoon H Cha WC Sim MS Carriere KC Impact of metformin use on lactate kinetics in patients with severe sepsis and septic shock Shock 2017 47 5 582 587 10.1097/SHK.0000000000000782 27792125
Park J, Hwang SY, Jo IJ, Jeon K, Suh GY, Lee TR, Yoon H, Cha WC, Sim MS, Carriere KC, et al. Impact of metformin use on lactate kinetics in patients with severe sepsis and septic shock. Shock. 2017;47(5):582–7.27792125 10.1097/SHK.0000000000000782
200. Liang H Ding X Li L Wang T Kan Q Wang L Sun T Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies Crit Care 2019 23 1 50 10.1186/s13054-019-2346-4 30777119
Liang H, Ding X, Li L, Wang T, Kan Q, Wang L, Sun T. Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies. Crit Care. 2019;23(1):50.30777119 10.1186/s13054-019-2346-4
201. Yang Q Zheng J Chen W Chen X Wen D Chen W Xiong X Zhang Z Association between preadmission metformin use and outcomes in intensive care unit patients with sepsis and type 2 diabetes: a cohort study Front Med (Lausanne) 2021 8 640785 10.3389/fmed.2021.640785 33855034
Yang Q, Zheng J, Chen W, Chen X, Wen D, Chen W, Xiong X, Zhang Z. Association between preadmission metformin use and outcomes in intensive care unit patients with sepsis and type 2 diabetes: a cohort study. Front Med (Lausanne). 2021;8:640785.33855034 10.3389/fmed.2021.640785
202. Foretz M Guigas B Viollet B Metformin: update on mechanisms of action and repurposing potential Nat Rev Endocrinol 2023 19 8 460 476 10.1038/s41574-023-00833-4 37130947
Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460–76.37130947 10.1038/s41574-023-00833-4
203. Howell JJ Hellberg K Turner M Talbott G Kolar MJ Ross DS Hoxhaj G Saghatelian A Shaw RJ Manning BD Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex Cell Metab 2017 25 2 463 471 10.1016/j.cmet.2016.12.009 28089566
Howell JJ, Hellberg K, Turner M, Talbott G, Kolar MJ, Ross DS, Hoxhaj G, Saghatelian A, Shaw RJ, Manning BD. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 2017;25(2):463–71.28089566 10.1016/j.cmet.2016.12.009
204. Xian H Liu Y Rundberg Nilsson A Gatchalian R Crother TR Tourtellotte WG Zhang Y Aleman-Muench GR Lewis G Chen W Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation Immunity 2021 54 7 1463 1477 e1411 10.1016/j.immuni.2021.05.004 34115964
Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, Zhang Y, Aleman-Muench GR, Lewis G, Chen W, et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity. 2021;54(7):1463-1477 e1411.34115964 10.1016/j.immuni.2021.05.004
205. Jager S Handschin C St-Pierre J Spiegelman BM AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha Proc Natl Acad Sci USA 2007 104 29 12017 12022 10.1073/pnas.0705070104 17609368
Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA. 2007;104(29):12017–22.17609368 10.1073/pnas.0705070104
206. Kim J Kwak HJ Cha JY Jeong YS Rhee SD Kim KR Cheon HG Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction J Biol Chem 2014 289 33 23246 23255 10.1074/jbc.M114.577908 24973221
Kim J, Kwak HJ, Cha JY, Jeong YS, Rhee SD, Kim KR, Cheon HG. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J Biol Chem. 2014;289(33):23246–55.24973221 10.1074/jbc.M114.577908
207. Wu W Wang S Liu Q Shan T Wang Y Metformin protects against lps-induced intestinal barrier dysfunction by activating AMPK pathway Mol Pharm 2018 15 8 3272 3284 10.1021/acs.molpharmaceut.8b00332 29969038
Wu W, Wang S, Liu Q, Shan T, Wang Y. Metformin protects against lps-induced intestinal barrier dysfunction by activating AMPK pathway. Mol Pharm. 2018;15(8):3272–84.29969038 10.1021/acs.molpharmaceut.8b00332
208. Ma T Tian X Zhang B Li M Wang Y Yang C Wu J Wei X Qu Q Yu Y Low-dose metformin targets the lysosomal AMPK pathway through PEN2 Nature 2022 603 7899 159 165 10.1038/s41586-022-04431-8 35197629
Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, Wu J, Wei X, Qu Q, Yu Y, et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature. 2022;603(7899):159–65.35197629 10.1038/s41586-022-04431-8
209. Cortes M Brischetto A Martinez-Campanario MC Ninfali C Dominguez V Fernandez S Celis R Esteve-Codina A Lozano JJ Sidorova J Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation Nat Commun 2023 14 1 7471 10.1038/s41467-023-42277-4 37978290
Cortes M, Brischetto A, Martinez-Campanario MC, Ninfali C, Dominguez V, Fernandez S, Celis R, Esteve-Codina A, Lozano JJ, Sidorova J, et al. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation. Nat Commun. 2023;14(1):7471.37978290 10.1038/s41467-023-42277-4
