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LHON-linked ND6 14484T\u2009&amp;gt;\u2009C (p.M64V) mutation affected structural components of complex I but its pathophysiology is poorly understood. The structural analysis of complex I revealed that the M64 forms a nonpolar interaction Y59 in the ND6, Y59 in the ND6 interacts with E34 of ND4L, and L60 of ND6 interacts with the Y114 of ND1. These suggested that the m.14484T\u2009&amp;gt;\u2009C mutation may perturb the structure and function of complex I. Mutant cybrids constructed by transferring mitochondria from lymphoblastoid cell lines of one Chinese LHON family into mtDNA-less (\u03c1o) cells revealed decreases in the levels of ND6, ND1 and ND4L. The m.14484T\u2009&amp;gt;\u2009C mutation may affect mitochondrial mRNA homeostasis, supported by reduced levels of SLIRP and SUPV3L1 involved in mRNA degradation and increasing expression of ND6, ND1 and ND4L genes. These alterations yielded decreased activity of complex I, respiratory deficiency, diminished mitochondrial ATP production and reduced membrane potential, and increased production of reactive oxygen species in the mutant cybrids. Furthermore, the m.14484T\u2009&amp;gt;\u2009C mutation promoted apoptosis, evidenced by elevating Annexin V-positive cells, release of cytochrome c into cytosol, levels in apoptotic proteins BAX, caspases 3, 7, 9 and decreasing levels in anti-apoptotic protein Bcl-xL in the mutant cybrids. Moreover, the cybrids bearing the m.14484T\u2009&amp;gt;\u2009C mutation exhibited the reduced levels of autophagy protein LC3, increased levels of substrate P62 and impaired PINK1\/Parkin-dependent mitophagy. Our findings highlighted the critical role of m.14484T\u2009&amp;gt;\u2009C mutation in the pathogenesis of LHON.<\/jats:p>","DOI":"10.1093\/hmg\/ddac109","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T08:10:18Z","timestamp":1652256618000},"page":"3299-3312","source":"Crossref","is-referenced-by-count":31,"title":["Leber\u2019s hereditary optic neuropathy-associated ND6 14484T\u2009&amp;gt;\u2009C mutation caused pleiotropic effects on the complex I, RNA homeostasis, apoptosis and mitophagy"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4922-4924","authenticated-orcid":false,"given":"Min","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang 325000 , China"},{"name":"Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035 , China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310058 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchun","family":"Ji","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310058 , China"},{"name":"Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinic Research Center for Child Health , Hangzhou, Zhejiang 310058 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-593X","authenticated-orcid":false,"given":"Liyao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310058 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuifang","family":"Hu","sequence":"additional","affiliation":[{"name":"Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035 , China"},{"name":"School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University , Wenzhou, Zhejiang 325027 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310058 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Q","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Rady Children\u2019s Hospital, University of California at San Diego School of Medicine , San Diego, California 92123 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-6736","authenticated-orcid":false,"given":"Min-Xin","family":"Guan","sequence":"additional","affiliation":[{"name":"Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035 , China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310058 , China"},{"name":"Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinic Research Center for Child Health , Hangzhou, Zhejiang 310058 , China"},{"name":"Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders , Hangzhou, Zhejiang 310058 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,14]]},"reference":[{"key":"2022093009400777900_ref1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/164_2017_2","article-title":"Leber hereditary optic neuropathy: Exemplar of an mtDNA disease","volume":"240","author":"Wallace","year":"2017","journal-title":"Handb. 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