{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:21:26Z","timestamp":1787498486798,"version":"build-2736575974"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2700902"],"award-info":[{"award-number":["2021YFC2700902"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970557"],"award-info":[{"award-number":["31970557"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171847"],"award-info":[{"award-number":["82171847"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900904"],"award-info":[{"award-number":["81900904"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children\u2019s Hospital, Zhejiang University School of Medicine","award":["Q21C0005"],"award-info":[{"award-number":["Q21C0005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Leber\u2019s hereditary optic neuropathy (LHON) is a maternally transmitted eye disease due to the degeneration of retinal ganglion cells (RGCs). Mitochondrial 11778G\u2009&amp;gt;\u2009A mutation is the most common LHON-associated mitochondrial DNA (mtDNA) mutation. Our recent studies demonstrated some LHON families manifested by synergic interaction between m.11778G\u2009&amp;gt;\u2009A mutation and YARS2 allele (c.572G\u2009&amp;gt;\u2009T, p.Gly191Val) encoding mitochondrial tyrosyl-tRNA synthetase. However, the RGC-specific effects of LHON-associated mtDNA mutations remain elusive and there is no highly effective therapy for LHON. Here, we generated patients-derived induced pluripotent stem cells (iPSCs) from fibroblasts derived from a Chinese LHON family (both m.11778G\u2009&amp;gt;\u2009A and c.572G\u2009&amp;gt;\u2009T mutations, only m.11778G\u2009&amp;gt;\u2009A mutation, and control subject). The c.572G\u2009&amp;gt;\u2009T mutation in iPSC lines from a syndromic individual was corrected by CRISPR\/Cas9. Those iPSCs were differentiated into neural progenitor cells and subsequently induced RGC-like cells using a stepwise differentiation procedure. Those RGC-like cells derived from symptomatic individual harboring both m.11778G\u2009&amp;gt;\u2009A and c.572G\u2009&amp;gt;\u2009T mutations exhibited greater defects in neuronal differentiation, morphology including reduced area of soma, numbers of neurites and shortened length of axons, electrophysiological properties than those in cells bearing only m.11778G\u2009&amp;gt;\u2009A mutation. Furthermore, these RGC-like cells revealed more drastic reductions in oxygen consumption rates, levels of mitochondrial ATP and increasing productions of reactive oxygen species than those in other cell models. These mitochondrial dysfunctions promoted the apoptotic process for RGC degenerations. Correction of YARS2 c.572G\u2009&amp;gt;\u2009T mutation rescued deficiencies of patient-derived RGC-like cells. These findings provide new insights into pathophysiology of LHON arising from RGC-specific mitochondrial dysfunctions and step toward therapeutic intervention for this disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddad001","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T17:02:53Z","timestamp":1672765373000},"page":"1539-1551","source":"Crossref","is-referenced-by-count":13,"title":["Nuclear modifier\n                    <i>YARS2<\/i>\n                    allele correction restored retinal ganglion cells-specific deficiencies in Leber\u2019s hereditary optic neuropathy"],"prefix":"10.1093","volume":"32","author":[{"given":"Jia-Rong","family":"Chen","sequence":"first","affiliation":[{"name":"Center for Mitochondrial Biomedicine , the Fourth Affiliated Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine , the Fourth Affiliated Hospital, , Hangzhou, Zhejiang , China"},{"name":"Division of Medical Genetics and Genomics , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine and National Clinical Research Center for Child Health , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biomedicine , the Fourth Affiliated Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine , the Fourth Affiliated Hospital, , Hangzhou, Zhejiang , China"},{"name":"Division of Medical Genetics and Genomics , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine and National Clinical Research Center for Child Health , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University , Wenzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchun","family":"Ji","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine and National Clinical Research Center for Child Health , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanna","family":"Lian","sequence":"additional","affiliation":[{"name":"Department of Neurology , the Fourth Affiliated Hospital, , Yiwu, Zhejiang , China"},{"name":"Zhejiang University School of Medicine , the Fourth Affiliated Hospital, , Yiwu, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University , Wenzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialing","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine and National Clinical Research Center for Child Health , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang Provincial Key Lab of Genetic and Developmental Disorder , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Yao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology , the Fourth Affiliated Hospital, , Yiwu, Zhejiang , China"},{"name":"Zhejiang University School of Medicine , the Fourth Affiliated Hospital, , Yiwu, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Qu","sequence":"additional","affiliation":[{"name":"School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University , Wenzhou, Zhejiang , China"}],"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":"Center for Mitochondrial Biomedicine , the Fourth Affiliated Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine , the Fourth Affiliated Hospital, , Hangzhou, Zhejiang , China"},{"name":"Division of Medical Genetics and Genomics , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Zhejiang University School of Medicine and National Clinical Research Center for Child Health , The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine , Hangzhou, Zhejiang , China"},{"name":"Zhejiang Provincial Key Lab of Genetic and Developmental Disorder , Hangzhou, Zhejiang , China"},{"name":"Joint Institute of Genetics and Genomic Medicine between Zhejiang University and University of Toronto, Zhejiang University , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"2023042013500662100_ref1","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.stem.2018.05.013","article-title":"Regenerating eye tissues to preserve and restore 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J. Mol. Sci."},{"key":"2023042013500662100_ref3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.preteyeres.2010.11.002","article-title":"Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies","volume":"30","author":"Yu-Wai-Man","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"2023042013500662100_ref4","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.ajo.2005.03.017","article-title":"Hereditary optic neuropathies: from the mitochondria to the optic nerve","volume":"140","author":"Newman","year":"2005","journal-title":"Am J. Ophthalmol."},{"key":"2023042013500662100_ref5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11940-010-0100-y","article-title":"Leber's hereditary optic neuropathy","volume":"13","author":"Sadun","year":"2011","journal-title":"Curr. Treat. Options Neurol."},{"key":"2023042013500662100_ref6","doi-asserted-by":"crossref","first-page":"eaaz7423","DOI":"10.1126\/scitranslmed.aaz7423","article-title":"Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy","volume":"12","author":"Yu-Wai-Man","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"2023042013500662100_ref7","first-page":"00174","article-title":"Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management","volume":"S1474\u20134422","author":"Newman","year":"2022","journal-title":"Lancet Neurol."},{"key":"2023042013500662100_ref8","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/humu.1380060405","article-title":"Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations","volume":"6","author":"Brown","year":"1995","journal-title":"Hum. Mutat."},{"key":"2023042013500662100_ref9","doi-asserted-by":"crossref","first-page":"D823","DOI":"10.1093\/nar\/gkl927","article-title":"An enhanced MITOMAP with a global mtDNA mutational phylogeny","volume":"35","author":"Ruiz-Pesini","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2023042013500662100_ref10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1136\/jmg.2007.054270","article-title":"Inherited mitochondrial optic neuropathies","volume":"46","author":"Yu-Wai-Man","year":"2009","journal-title":"J. Med. Genet."},{"key":"2023042013500662100_ref11","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.3201231","article-title":"Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy","volume":"242","author":"Wallace","year":"1988","journal-title":"Science"},{"key":"2023042013500662100_ref12","doi-asserted-by":"crossref","first-page":"4778","DOI":"10.1167\/iovs.14-16158","article-title":"Prevalence of mitochondrial ND4 mutations in 1281 Han Chinese subjects with Leber's hereditary optic neuropathy","volume":"56","author":"Jiang","year":"2015","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2023042013500662100_ref13","doi-asserted-by":"crossref","first-page":"39831","DOI":"10.1074\/jbc.M006476200","article-title":"Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation","volume":"275","author":"Brown","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2023042013500662100_ref14","doi-asserted-by":"crossref","first-page":"13155","DOI":"10.1074\/jbc.271.22.13155","article-title":"Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy","volume":"271","author":"Hofhaus","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2023042013500662100_ref15","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1093\/hmg\/ddv498","article-title":"The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation","volume":"25","author":"Jiang","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2023042013500662100_ref16","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1093\/hmg\/ddy450","article-title":"Contribution of mitochondrial ND1 3394T&gt;C mutation to the phenotypic manifestation of Leber's hereditary optic neuropathy","volume":"28","author":"Ji","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2023042013500662100_ref17","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1172\/JCI134965","article-title":"PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy","volume":"130","author":"Yu","year":"2020","journal-title":"J. Clin. Invest."},{"key":"2023042013500662100_ref18","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/S0002-9394(14)76784-4","article-title":"The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation","volume":"111","author":"Newman","year":"1991","journal-title":"Am J. 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Sci."},{"key":"2023042013500662100_ref21","doi-asserted-by":"crossref","first-page":"a041282","DOI":"10.1101\/cshperspect.a041282","article-title":"From bench to bedside-delivering gene therapy for Leber hereditary optic neuropathy","volume":"12","author":"Chen","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"2023042013500662100_ref22","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13287-015-0264-1","article-title":"Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets","volume":"7","author":"Chen","year":"2016","journal-title":"Stem Cell Res Ther"},{"key":"2023042013500662100_ref23","doi-asserted-by":"crossref","first-page":"111124","DOI":"10.1016\/j.celrep.2022.111124","article-title":"Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy","volume":"40","author":"Danese","year":"2022","journal-title":"Cell Rep."},{"key":"2023042013500662100_ref24","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/stem.2356","article-title":"Stepwise differentiation of retinal ganglion cells from human pluripotent stem cells enables analysis of glaucomatous neurodegeneration","volume":"34","author":"Ohlemacher","year":"2016","journal-title":"Stem Cells"},{"key":"2023042013500662100_ref25","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1093\/hmg\/ddac190","article-title":"Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy","volume":"32","author":"Nie","year":"2022","journal-title":"Hum. 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Genet."},{"key":"2023042013500662100_ref37","doi-asserted-by":"crossref","first-page":"100437","DOI":"10.1016\/j.jbc.2021.100437","article-title":"An animal model for mitochondrial tyrosyl-tRNA synthetase deficiency reveals links between oxidative phosphorylation and retinal function","volume":"296","author":"Jin","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2023042013500662100_ref38","doi-asserted-by":"crossref","first-page":"19292","DOI":"10.1074\/jbc.RA119.010598","article-title":"Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNASer(UCN) 7511A&gt;G mutation","volume":"294","author":"Fan","year":"2019","journal-title":"J. Biol. 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