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Key pathogenic mechanisms include heteroplasmy driven threshold effects, excess reactive oxygen species, disrupted mitochondrial dynamics and mitophagy, abnormal calcium signaling, and compromised mtDNA repair, which together cause tissue\u2010specific energy failure in high demand organs. Recent advances have expanded the therapeutic landscape. Precision mitochondrial genome editing\u2014using mitochondrial zinc finger nucleases, mitochondrial transcription activator\u2010like effector nucleases, DddA\u2010derived cytosine base editor, and other base editing tools\u2014enables targeted correction or rebalancing of mutant genomes, while highlighting challenges of delivery and off\u2010target effects. In parallel, metabolic modulators (e.g., coenzyme Q10, idebenone, EPI\u2010743) aim to restore bioenergetics, and mitochondrial replacement technologies and transplantation are being explored. Despite these promising strategies, major challenges remain, including off\u2010target effects, precise delivery, and ethical considerations. Addressing these issues through multidisciplinary research and clinical translation holds promise for transforming mitochondrial disease management and improving patient outcomes. By bridging the understanding of mitochondrial dysfunction with advanced therapeutic interventions, this review aims to shed light on effective solutions for managing these complex disorders.<\/jats:p>","DOI":"10.1002\/mco2.70385","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T08:43:34Z","timestamp":1757666614000},"source":"Crossref","is-referenced-by-count":13,"title":["Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances"],"prefix":"10.1002","volume":"6","author":[{"given":"Jialun","family":"Mei","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Institute of Microsurgery on Extremities and Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Institute of Microsurgery on Extremities and Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Institute of Microsurgery on Extremities and Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Institute of Microsurgery on Extremities and Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Surgery Department of Surgery The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Institute of Microsurgery on Extremities and Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4820-8524","authenticated-orcid":false,"given":"Junjie","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Institute of Microsurgery on Extremities and Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"issue":"4","key":"e_1_2_12_2_1","first-page":"943","article-title":"The Origin of Mitochondrial Cristae From Alphaproteobacteria","volume":"34","author":"Mu\u00f1oz\u2010G\u00f3mez S. 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