
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.19.608708
preprint
1
Article
Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology
Barnett Daniel http://orcid.org/0000-0002-1340-4413

Zimmer Till S. http://orcid.org/0000-0002-6869-3697

Booraem Caroline http://orcid.org/0009-0000-3294-6253

Palaguachi Fernando http://orcid.org/0000-0001-5403-7093

Meadows Samantha M. http://orcid.org/0000-0002-0954-5379

Xiao Haopeng http://orcid.org/0000-0002-4166-647X

Chouchani Edward T. http://orcid.org/0000-0002-9203-8094

Orr Anna G. http://orcid.org/0000-0002-4036-4277

Orr Adam L. http://orcid.org/0000-0003-0338-7709

20 8 2024
2024.08.19.608708https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.19.608708
nihpp-2024.08.19.608708.pdf
Abstract

Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with mitochondrial ROS imaging and multiomic profiling, we found that CIII is the dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity in a non-cell- autonomous manner. As proof-of-concept, suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
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