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Beyond energy production, mitochondria function as critical regulators of metabolic homeostasis, intracellular signaling networks, and programmed cell death pathways. The mitochondrial genome comprises 37 genes encoding 13 OXPHOS subunits, 22 transfer RNAs, and 2 ribosomal RNAs, all transcribed and translated within the organelle. Mitochondrial DNA integrity becomes compromised through diverse pathological stimuli, including metabolic dysregulation, oxidative stress, and inflammatory cascades, contributing to disease pathogenesis across multiple organ systems. This review synthesizes current knowledge on the multifaceted roles of mtDNA in health and disease. We propose a framework of three interconnected mechanisms through which mtDNA exerts its effects: (1) retrograde signaling to the nucleus, reprogramming nuclear gene expression; (2) cytosolic and extracellular release of mtDNA as a damage\u2010associated molecular pattern (DAMP), activating innate immune pathways like cGAS\u2010STING and NLRP3; and (3) intrinsic epigenetic modifications that directly modulate mitochondrial gene expression. We critically evaluate the evidence linking mtDNA alterations to a spectrum of diseases, including cancer, cardiovascular and metabolic disorders, neurodegeneration, and psychiatric conditions. We conclude that a comprehensive understanding of mtDNA's multifaceted nature, moving beyond its perception as a mere DAMP, is essential for translating mitochondrial biology into effective clinical interventions.<\/jats:p>","DOI":"10.1096\/fj.202600927r","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:49:31Z","timestamp":1791190171000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Genetic and Epigenetic Mechanisms of\n                    <scp>mtDNA<\/scp>\n                    in Regulation of Inflammation and Metabolism"],"prefix":"10.1096","volume":"40","author":[{"given":"Yulin","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Duan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-4287","authenticated-orcid":false,"given":"Yifei","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10112898"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-1473"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05292"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3275"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.02.001"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051838"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.2741\/4535"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.02.004"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201949612"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5407.1482"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/290457a0"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2020.102916"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14081862"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.11.050"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ircmb.2021.04.001"},{"issue":"14","key":"e_1_2_11_17_1","first-page":"5378","article-title":"Repair of 8\u2010Oxodeoxyguanosine Lesions in Mitochondrial DNA Depends on the Oxoguanine Dna Glycosylase (OGG1) Gene and 8\u2010Oxoguanine Accumulates in the Mitochondrial DNA of OGG1\u2010Defective Mice","volume":"61","author":"Souza\u2010Pinto N. 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