==== Front Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.39812 Genetics Oncology Mitochondrial Deoxyribonucleic Acid (mtDNA), Maternal Inheritance, and Their Role in the Development of Cancers: A Scoping Review Muacevic Alexander Adler John R Vadakedath Sabitha 1 Kandi Venkataramana 2 CA Jayashankar 3 Vijayan Swapna 4 Achyut Kushal C 5 Uppuluri Shivani 3 Reddy Praveen Kumar K 6 Ramesh Monish 3 Kumar P Pavan 6 1 Biochemistry, Prathima Institute of Medical Sciences, Karimnagar, IND 2 Clinical Microbiology, Prathima Institute of Medical Sciences, Karimnagar, IND 3 Internal Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, IND 4 Pediatrics, Sir CV Raman General Hospital, Bengaluru, IND 5 Internal Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND 6 General Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, IND Sabitha Vadakedath tejaswani19@gmail.com 1 6 2023 6 2023 15 6 e3981231 5 2023 Copyright © 2023, Vadakedath et al. 2023 Vadakedath et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from https://www.cureus.com/articles/150482-mitochondrial-deoxyribonucleic-acid-mtdna-maternal-inheritance-and-their-role-in-the-development-of-cancers-a-scoping-review Mitochondrial DNA (mtDNA) is a small, circular, double-stranded DNA inherited from the mother during fertilization. Evolutionary evidence supported by the endosymbiotic theory identifies mitochondria as an organelle that could have descended from prokaryotes. This may be the reason for the independent function and inheritance pattern shown by mtDNA. The unstable nature of mtDNA due to the lack of protective histones, and effective repair systems make it more vulnerable to mutations. The mtDNA and its mutations could be maternally inherited thereby predisposing the offspring to various cancers like breast and ovarian cancers among others. Although mitochondria are considered heteroplasmic wherein variations among the multiple mtDNA genomes are noticed, mothers can have mitochondrial populations that are homoplasmic for a given mitochondrial mutation. Homoplasmic mitochondrial mutations may be transmitted to all maternal offspring. However, due to the complex interplay between the mitochondrial and nuclear genomes, it is often difficult to predict disease outcomes, even with homoplasmic mitochondrial populations. Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency witnessed during the transmission of mtDNA from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be demonstrated. Despite initially thought to be limited to the germline, there is evidence that blockages exist in different cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. In this review, we comprehensively discuss the potential mechanisms through which mtDNA undergoes mutations and the maternal mode of transmission that contributes to the development of tumors, especially breast and ovarian cancers. cancer inheritance mtdna endosymbiotic theory mitochondrial dna ==== Body pmcIntroduction and background Mitochondrial deoxyribonucleic acid (mtDNA) is a small circular DNA found within mitochondria present in the cytoplasm of a cell. This DNA is supplementary to the nucleic acid material found in the nucleus of each cell. The mtDNA codes for 37 genes that promote the proper functioning of some cells. The mitochondria synthesize adenosine triphosphate (ATP) through oxidative phosphorylation and encode information for the synthesis of enzymes, transfer ribonucleic acid (tRNA), and ribosomal RNA (rRNA) [1]. Disorders of mtDNA and mutations in its genes can predispose to health problems like age-related hearing loss, diabetes, and brain, heart, and liver failure, among other conditions [2]. Moreover, mtDNA and its associated mitochondrial disorders can predispose people to different types of cancers including lymphomas, leukemias, and breast, intestine, liver, and kidney tumors, among others [1, 3]. However, the mechanisms behind carcinogenesis are not yet adequately elaborated.  From the results of evolutionary and genetic studies, mtDNA has been shown to be inherited from the mother during fertilization [4]. Additionally, studies have observed some important characteristics of mtDNA like high mutation rates, increased copy numbers in a cell, and unable to undergo recombination [5-7]. According to endosymbiotic theory, the origin of eukaryotic cells has been tracked back to the prokaryotes. It was Lynn Margulis who proposed the endosymbiotic theory in the 1960s [8]. This theory puts forth a gradual process that occurs over a long period of time for the development of eukaryotic cells from the prokaryotes [9]. The mitochondria, plastids, and chloroplasts could have descended from free-living prokaryotes [9]. The endosymbiotic theory presumes that complex multicellular organisms including humans have a small mitochondrial genome that is being generated and transferred through evolution, probably from the prokaryotes [10]. It has been hypothesized that some of the organelles of eukaryotic cells could have developed from the prokaryotes like bacteria. The early eukaryotic cells lacked mitochondria, but during evolution, these cells may have ingested the aerobic bacteria that had started living in symbiosis. During the course of evolution, the ingested aerobic bacteria lost their cell walls and may have developed into mitochondria [11]. The diagrammatic representation of the proposed evolution of mtDNA is shown in Figure 1. Figure 1 Endosymbiont theory depicting the evolution of mitochondria from prokaryotes. Note: This figure has been created by the authors ATP, adenosine triphosphate Review Human mtDNA contains 16,569 base pairs and encodes 13 proteins. The mtDNA has a heavy strand and a light strand wherein the heavy strand is guanine rich and encodes 12 subunits. The light strand is rich in cytosine and encodes one subunit that performs oxidative phosphorylation. The regulation of the entire mtDNA genome is at the site of origin of replication of these strands [12]. The hyper diversity is the reason for the high mutational rate seen in mtDNA and vice versa. This hyper-diverse mtDNA causes unusual variations in DNA sequence, promoting coding variations, gene rearrangements, recombination, and finally high mtDNA substitution rates [13]. The initial transcription of mtDNA takes place on a displacement loop (D-loop) that has unusual bases like dihydro uracil, and hence it is the more susceptible region to mutations [14-15]. Generally, the hypervariable regions help in the anchoring of proteins to the membrane, protein-protein interactions, and protein signaling not specific to mtDNA. These regions have variations in tandem repeats seen mostly on the D-loop of mtDNA. Tandem repeats are frequently observed sequences on DNA. They are more prone to mispairing of bases known as ‘slipped strand mispairing.’ This may be the reason for the inappropriate mismatch repair (MMR) seen in mtDNA [16]. It was assumed that the eukaryotic mtDNA has an inefficient repair system but recent identification of the mutHLS (consisting of mutH, mutL, and mutS mutation detection and repair proteins) system has confirmed the potential role of mutHLS system in the repair process. Within the mtDNA, mutHLS repairs mismatch, strand break, insertion, and deletion of bases repair through endonuclease activity [17-18].  Less efficient MMR is seen in mtDNA compared to nuclear DNA [19]. Therefore, mtDNA could suffer from lesions, undergo deletions and insertions, and develop mutations that could predispose to carcinogenesis. The identification of mismatches and initiation of repair is very much required for genome stability. Defective MMR leads to the loss of gene activities. This further leads to microsatellite instability, elevates spontaneous mutation rate, and accelerates tumor development and progression as shown in Figure 2. Figure 2 Effects of mismatch repair on mitochondrial DNA mutations and cancer. Note: This figure has been created by the authors MMR, mismatch repair; DNA, deoxyribonucleic acid Another mechanism by which the defects in mtDNA can cause carcinogenesis is the generation of reactive oxygen species (ROS) during the process of oxidative phosphorylation [20-21]. Production of ROS by the mitochondria further leads to alterations in cellular vitality and metabolite concentrations. In this process, the ROS stimulates the Rac1 (Ras-related C3 botulinum toxin substrate 1) protein which acts on the vascular endothelial cells. This causes the release of nitric oxide (NO) that results in antiatherogenic effects like vasodilatation and inhibition of platelet and leukocyte aggregation. Moreover, this process results in the loss of cell-to-cell adhesion and loosens the endothelial integrity, and transforms the normal cells into cancer cells. The method of ROS-dependent carcinogenesis is shown in Figure 3. Figure 3 Role of ROS in the development of cancer. Note: This figure has been created by the authors ROS, reactive oxygen species; Rac1, Ras-related C3 botulinum toxin substrate 1; NO, nitric oxide The nuclear genome supplies protein for mitochondrial replication and gene expression. The mutations to these nuclear genomes not only alter mitochondrial function but also influences carcinogenesis and progression. It was found that the D-loop region and mitochondrial cytochrome b (MT-CYB) gene are specific sites of mtDNA where mutations are common [22-23]. The D-loop of mtDNA is required for transcription and gene expression. The strand/primer for initiation of transcription provides an additional strand that makes it a triple-strand DNA structure. This makes mtDNA more susceptible to the mutation of somatic cells that invariably lead to cancers [24]. This influences copy number of cells (variations in a repeated sequence of genes) as well as the regulation of mitochondria. The MT-CYB gene provides the necessary information for the synthesis of cytochrome b protein of complex III involved in oxidative phosphorylation [20, 23]. This highly variable nature of the MT-CYB gene is also the reason for the development of cancers. It was identified that oral cancers are primarily due to mtDNA mutations [23]. But it is unclear whether it is D-loop region or MT-CYB gene mutations that lead to pathological consequences in cancer. Hence it was suggested that mtDNA could be used as a biomarker for the early identification of cancers [23]. The role of the MT-CYB gene in the development of mitochondrial diseases and cancers is shown in Figure 4. Figure 4 Role of MT-CYB gene in the development of mitochondrial diseases and cancer. Note: This figure has been created by the authors MT-CYB, mitochondrial cytochrome b; mtDNA, mitochondrial DNA mtDNA and maternal inheritance The mitochondrial genome is independent of its inheritance pattern compared to chromosomal inheritance. Recent research had identified that paternal mtDNA is eliminated through various mechanisms which include mitophagy, and autophagy-independent degradation, among others. In mitophagy, aged and dysfunctional mitochondria are removed by lysosomal activity and/or proteasomal pathways at the embryonal stage [25-26]. Animal studies have suggested that the paternal mitochondria and the mtDNA could be eliminated by autophagosome-based sperm organelle mechanisms [27-29]. Other mechanisms like mitochondrial endonuclease-mediated elimination of paternal mtDNA have also been implicated in the maternal inheritance of mtDNA [30]. This enables uniparental inheritance which in turn keeps deleterious mutations of DNA genes at their location whilst restricting their spread [31-32]. Mitochondrial DNA (mtDNA) also contributes to the inheritance of cancer-susceptible alleles, loss of heterozygosity (two different genes) of inherited and mutated susceptible genes, and inactivation of tumor suppressor genes by deletion, insertion, or gene rearrangement. Additionally, biallelic inactivation (recessive), and heteroplasmy of mtDNA hold both abnormal and normal mitochondrial genomes due to unequal segregation [33-34]. The heteroplasmic nature of mtDNA leads to a genetic bottleneck which predicts that little mtDNA is transferred to the next generation limiting genetic variations in the family [35-36]. In a recent observation, it has been identified that the mitochondria meet the endoplasmic reticulum (ER) for the exchange of nutrients like calcium and glucose. Additionally, ER has been noted to assist in mitochondrial fusion and fission. Dysplasia of mitochondria in the neurons was found to predispose children to hereditary conditions like spastic paraplegias [37-38]. Influence of mtDNA in ovarian cancer and breast cancer Current evidence suggests that there is an increasing frequency of hereditary breast and ovarian cancers [39]. Additionally, there is an increased awareness of gene mutations that could predispose to the familial transfer of cancers [40]. However, there is a scarcity of such information regarding the role of mtDNA and its influence on the development of cancers. The D-loop of mtDNA is more prone to mutations in breast and ovarian cancers. The mitochondrial microsatellite instability (mtMSI) and variations in CA (cytosine, adenine) repeats were also observed in ovarian and breast carcinoma. The inefficient MMR after malignant transformation may contribute to mtMSI. The mtMSI is observed in mononucleotide repeats at nucleotide positions 303-309. This region is the site where replication primer binds, making a defective DNA repair system. In a previous study, it was found that homo polymorphic nucleotide (variant forms of specific nucleotide sequence) tracts of mtDNA are more prone to errors due to the low frameshift (addition/deletion of bases) mutations. Moreover, the fidelity of DNA polymerase gamma (PLOG) that carries out the mtDNA replication process is lower than that found in the nucleus and is not severely affected [41-46]. In a recent report, it was noticed that mitochondria may play a significant role in the development, metastasis, chemotherapy resistance, and treatment of ovarian cancers [47]. The mitochondrial ribosomal proteins (MRPs) including the MRPL15 were found to be associated with the development of ovarian cancer. Moreover, this protein was found to be efficient in predicting the prognosis [48]. Damage to the mitochondria present in the ovarian germ and somatic cells may lead to the transfer of mitochondrial non-coding RNAs (ncRNAs) into the nucleus. This could predispose to early ovarian aging and resultant adverse effects including hormonal imbalances and tumorigenesis [49]. The abnormal transmission of mtDNA into the nuclear DNA was found to correlate with the development of breast cancer [50]. An association of mitochondrial D310 mutation was found to correlate with the development of various solid organ cancers including breast cancer [51]. Current research perspectives Two different mtDNA variants/mutations were identified wherein the mutations that cause the formation of tumors are called inducers and those mtDNA mutations that facilitate the survival of tumor cells are called adaptors. The mtDNA mutations may be of three types based on their origins including those which are inherited and undergo familial transfer, mutations that happen within the cell, and ancient but transferable mtDNA variations [52]. Recent research had also suggested that better mitochondrial health can be instrumental in preventing replication errors and regulating apoptotic activities [53]. Studies have noted that mtDNA mutations, dysregulation of mtDNA, and disturbances in the communication between nuclear DNA and mtDNA may affect cellular health and in turn, predispose to carcinogenesis [54]. A recent hypothesis also suggested that the mitochondria may under the influence of microbial pathogens can transform themselves into super-power cells or immortal cancer cells that enable tumor formation [55]. In view of the potential role of mtDNA in aging and diseases including cancers, the role of gene editing in therapeutic management was being explored [56]. The aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme was found to regulate acetaldehyde toxicity within the cell and was suggested as a potential biomarker for diagnosis, metastasis, and prognosis of cancer. Additionally, abnormalities in ALDH2 and associated gene polymorphisms (single nucleotide polymorphisms-rs671) were noted to influence tumorigenesis and therefore should be considered as potential therapeutic targets [57]. Drugs like nilotinib, salinomycin, tigecycline, and eupatilin among others targeting mitochondrial dysfunctional pathways are being explored for their role in the treatment and management of ovarian cancer [58]. Given that the functional characteristics of somatic mtDNA are not sufficiently elucidated, it is impractical to understand the variations and mutations of mtDNA and its relationship with cancers [59-61]. Conclusions The mtDNA is inherited uniparentally probably owing to the loss of paternal mtDNA during fertilization. The unique nature of mtDNA to synthesize its proteins and its independent inheritance patterns makes it a strong maternal factor. The unstable nature of replication machinery with a defective repair system makes mtDNA more prone to mutations and tumorigenesis. The inheritance patterns seen in ovarian and breast cancers are solely dependent on the frequency of mtDNA mutations and their ability to utilize different repair mechanisms in various tumor cells. Therefore, it is extremely essential for the researchers and the physicians involved in cancer diagnosis, treatment, and management to improve the understanding of the potential role of mtDNA in the development, diagnosis, prevention, and cure of cancers. The authors have declared that no competing interests exist. ==== Refs References 1 Mitochondrial DNA 2 2023 2020 https://medlineplus.gov/genetics/chromosome/mitochondrial-dna/ 2 The mitochondrion: a perpetrator of acquired hearing loss Hear Res Böttger EC Schacht J 12 19 303 2013 23361190 3 The role of mitochondria in carcinogenesis Int J Mol Sci Kozakiewicz P Grzybowska-Szatkowska L Ciesielka M 5100 22 2021 34065857 4 Maternal inheritance of mammalian mitochondrial DNA Nature Hutchison CA 3rd Newbold JE Potter SS 536 538 251 1974 4423884 5 Maternal ancestry and population history from whole mitochondrial genomes Investig Genet Kivisild T 3 6 2015 6 Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes Nature Wei W Schon KR Elgar G 105 114 611 2022 36198798 7 Mitochondrial DNA and human evolution Annu Rev Genomics Hum Genet Pakendorf B Stoneking M 165 183 6 2005 16124858 8 On the origin of mitosing cells J Theor Biol Sagan L 255 274 14 1967 11541392 9 Lynn Margulis and the origin of the eukaryotes J Theor Biol Cornish-Bowden A 1 434 2017 28992902 10 Sequence and organization of the human mitochondrial genome Nature Anderson S Bankier AT Barrell BG 457 465 290 1981 7219534 11 The endosymbiotic theory 4 2023 3 2023 2022 https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Kaiser)/Unit_4%3A_Eukaryotic_Microorganisms_and_Viruses/07%3A_The_Eukaryotic_Cell/7.8%3A_The_Endosymbiotic_Theory 12 Relation between mitochondrial DNA hyperdiversity, mutation rate and mitochondrial genome evolution in Melarhaphe neritoides (Gastropoda: Littorinidae) and other Caenogastropoda Sci Rep Fourdrilis S de Frias Martins AM Backeljau T 17964 8 2018 30568252 13 The mitochondrial genome: structure, transcription, translation and replication Biochim Biophys Acta Taanman JW 103 123 1410 1999 10076021 14 Clinical significance of the D-loop gene mutation in mitochondrial DNA in laryngeal cancer Onco Targets Ther Wang L Cheng HX Zhou YH 3461 3466 14 2021 34079291 15 Molecular origins of rapid and continuous morphological evolution Proc Natl Acad Sci USA Fondon JW 3rd Garner HR 18058 18063 101 2004 15596718 16 Why do mammalian mitochondria possess a mismatch repair activity? FEBS Lett Mason PA Lightowlers RN 6 9 554 2003 14596905 17 DNA mismatch repair and its many roles in eukaryotic cells Mutat Res Rev Mutat Res Liu D Keijzers G Rasmussen LJ 174 187 773 2017 28927527 18 Repair of mtDNA in vertebrates Am J Hum Genet Bogenhagen DF 1276 1281 64 1999 10205257 19 Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy J Cell Physiol Yang Y Karakhanova S Hartwig W 2570 2581 231 2016 26895995 20 Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer Cancer Res Dasgupta S Hoque MO Upadhyay S 700 706 68 2008 18245469 21 Number of somatic mutations in the mitochondrial D-loop region indicates poor prognosis in breast cancer, independent of TP53 mutation Cancer Genet Cytogenet Kuo SJ Chen M Ma GC 94 101 201 2010 20682393 22 A neonatal polyvisceral failure linked to a de novo homoplasmic mutation in the mitochondrially encoded cytochrome b gene Mitochondrion Fragaki K Procaccio V Bannwarth S 346 352 9 2009 19563916 23 Validation of next-generation sequencing of entire mitochondrial genomes and the diversity of mitochondrial DNA mutations in oral squamous cell carcinoma PLoS One Kloss-Brandstätter A Weissensteiner H Erhart G 0 10 2015 24 Mitochondria and the hallmarks of cancer FEBS J Giampazolias E Tait SW 803 814 283 2016 26607558 25 Degradation of paternal mitochondria via mitophagy Biochim Biophys Acta Gen Subj Sasaki T Sato M 129886 1865 2021 33636253 26 Allophagy, or how the embryo eliminates mitochondria and other paternal organelles (Article in French) Med Sci (Paris) Rawi SA Galy V 343 346 28 2012 22549853 27 Autophagosomal sperm organelle clearance and mtDNA inheritance in C. elegans Adv Anat Embryol Cell Biol Merlet J Rubio-Peña K Al Rawi S 1 23 231 2019 30467692 28 Multiple roles of endocytosis and autophagy in intracellular remodeling during oocyte-to-embryo transition Proc Jpn Acad Ser B Phys Biol Sci Sato K 207 221 98 2022 29 Post-fertilisation sperm mitophagy: the tale of mitochondrial eve and Steve Reprod Fertil Dev Sutovsky P Song WH 56 63 30 2017 29539303 30 Mitochondrial endonuclease G mediates breakdown of paternal mitochondria upon fertilization Science Zhou Q Li H Li H 394 399 353 2016 27338704 31 Mitochondrial dynamics in health and disease FEBS Lett Yapa NM Lisnyak V Reljic B 1184 1204 595 2021 33742459 32 Maternal inheritance of mitochondrial DNA: degradation of paternal mitochondria by allogeneic organelle autophagy, allophagy Autophagy Sato M Sato K 424 425 8 2012 22302002 33 Doubly uniparental inheritance: two mitochondrial genomes, one precious model for organelle DNA inheritance and evolution DNA Cell Biol Passamonti M Ghiselli F 79 89 28 2009 19196051 34 Two genetic hits (more or less) to cancer Nat Rev Cancer Knudson AG 157 162 1 2001 11905807 35 Biparental inheritance of mitochondrial DNA in humans Proc Natl Acad Sci USA Luo S Valencia CA Zhang J 13039 13044 115 2018 30478036 36 A genetic bottleneck of mitochondrial DNA during human lymphocyte development Mol Biol Evol Tang Z Lu Z Chen B 0 39 2022 37 Reorganization, specialization, and degradation of oocyte maternal components for early development Reprod Med Biol Satouh Y Sato K 0 22 2023 38 Lipids in the physiopathology of hereditary spastic paraplegias Front Neurosci Darios F Mochel F Stevanin G 74 14 2020 32180696 39 Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis Breast Cancer Yoshida R 1167 1180 28 2021 32862296 40 Implementation of multigene panel testing for breast and ovarian cancer in South Africa: a step towards excellence in oncology for the public sector Front Oncol van der Merwe NC Ntaita KS Stofberg H 938561 12 2022 36568162 41 The mitochondrial DNA genetic bottleneck: inheritance and beyond Essays Biochem Zhang H Burr SP Chinnery PF 225 234 62 2018 29880721 42 Frequent mutations in the mitochondrial control region DNA in breast tissue Cancer Lett Rosson D Keshgegian AA 89 94 215 2004 15374637 43 Ovarian cancer: a landscape of mitochondria with emphasis on mitochondrial dynamics Int J Mol Sci De Rasmo D Cormio A Cormio G 1224 24 2023 36674740 44 Research highlights on contributions of mitochondrial DNA microsatellite instability in solid cancers - an overview Contemp Oncol (Pozn) Yusoff AA Radzak SM Khair SZ 8 26 26 2022 35506039 45 The fidelity of human DNA polymerase gamma with and without exonucleolytic proofreading and the p55 accessory subunit J Biol Chem Longley MJ Nguyen D Kunkel TA 38555 38562 276 2001 11504725 46 A single mutation in human mitochondrial DNA polymerase Pol gammaA affects both polymerization and proofreading activities of only the holoenzyme J Biol Chem Lee YS Johnson KA Molineux IJ 28105 28116 285 2010 20513922 47 Mitochondrial integration and ovarian cancer chemotherapy resistance Exp Cell Res Shen L Xia M Zhang Y 112549 401 2021 33640393 48 MRPL15 is a novel prognostic biomarker and therapeutic target for epithelial ovarian cancer Cancer Med Xu H Zou R Li F 3655 3673 10 2021 33934540 49 Ovarian aging: role of pituitary-ovarian axis hormones and ncRNAs in regulating ovarian mitochondrial activity Front Endocrinol (Lausanne) Colella M Cuomo D Peluso T 791071 12 2021 34975760 50 Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells Genome Res Ju YS Tubio JM Mifsud W 814 824 25 2015 25963125 51 Mitochondrial D310 mutation as clonal marker for solid tumors Virchows Arch Geurts-Giele WR Gathier GH Atmodimedjo PN 595 602 467 2015 26276353 52 Mitochondrial DNA variation and cancer Nat Rev Cancer Kopinski PK Singh LN Zhang S 431 445 21 2021 34045735 53 Metabolic health, mitochondrial fitness, physical activity, and cancer Cancers (Basel) Clemente-Suárez VJ Martín-Rodríguez A Redondo-Flórez L 814 15 2023 36765772 54 Functional role of mitochondrial DNA in cancer progression Int J Mol Sci Lin YH Lim SN Chen CY 1659 23 2022 35163579 55 From pathogens to cancer: are cancer cells evolved mitochondrial super cells? Diagnostics (Basel) Balzanelli MG Distratis P Lazzaro R 813 13 2023 36832301 56 The mitochondrial genome in aging and disease and the future of mitochondrial therapeutics Biomedicines Saravanan S Lewis CJ Dixit B 490 10 2022 35203698 57 The role of ALDH2 in tumorigenesis and tumor progression: targeting ALDH2 as a potential cancer treatment Acta Pharm Sin B Zhang H Fu L 1400 1411 11 2021 34221859 58 Mitochondrial dysfunction pathway alterations offer potential biomarkers and therapeutic targets for ovarian cancer Oxid Med Cell Longev Shen L Zhan X 5634724 2022 2022 35498135 59 Mitochondrial DNA: the overlooked oncogenome? BMC Biol Gammage PA Frezza C 53 17 2019 31286943 60 Mitochondrial DNA is a major source of driver mutations in cancer Trends Cancer Kim M Mahmood M Reznik E 1046 1059 8 2022 36041967 61 Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade bioRxiv Mahmood M Liu EM Shergold AL 2023