{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:28:39Z","timestamp":1787498919725,"version":"build-2736575974"},"reference-count":93,"publisher":"Wiley","issue":"41","license":[{"start":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T00:00:00Z","timestamp":1726099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"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"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNA\n                    <jats:sup>Glu<\/jats:sup>\n                    14693A &gt; G and\n                    <jats:italic>ND6<\/jats:italic>\n                    14484T &gt; C mutations in three Chinese families affected by LHON is investigated. The m.14693A &gt; G mutation nearly abolishes the pseudouridinylation at position 55 of tRNA\n                    <jats:sup>Glu<\/jats:sup>\n                    , leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the\n                    <jats:italic>ND6<\/jats:italic>\n                    14484T &gt; C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual\u2010mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.\n                  <\/jats:p>","DOI":"10.1002\/advs.202401856","type":"journal-article","created":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T11:07:21Z","timestamp":1726139241000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitochondrial tRNA\n                    <sup>Glu<\/sup>\n                    14693A &gt; G Mutation, an \u201cEnhancer\u201d to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy"],"prefix":"10.1002","volume":"11","author":[{"given":"Lihao","family":"Jin","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingyi","family":"Gan","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"He","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchenlu","family":"Xiang","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinsheng","family":"Wei","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Eriani","sequence":"additional","affiliation":[{"name":"Architecture et R\u00e9activit\u00e9 de l'ARN UPR9002 Centre National de la Recherche Scientifique Universit\u00e9 de Strasbourg Institut de Biologie Mol\u00e9culaire et Cellulaire  2 all\u00e9e Konrad Roentgen Strasbourg 67084 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchun","family":"Ji","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Xin","family":"Guan","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6665-5884","authenticated-orcid":false,"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University  Yiwu 322000 China"},{"name":"Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health  Hangzhou 310058 China"},{"name":"Institute of Genetics Zhejiang University International School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,12]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1177\/1120672120936592"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111124"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-0972-1552"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.06.051"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac190"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddad001"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-20695"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2022.05.003"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.06.051"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2013-304140"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09619-z"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.050"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(92)90479-5"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-15385-2"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2009.08.010"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006476200"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1995.2563"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3341\/jkos.2012.53.1.151"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2013.05.002"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.04.025"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100816"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0665"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.128702"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2006.02.014"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi0123s44"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.03.189"},{"key":"e_1_2_9_27_1","first-page":"693","volume":"38","author":"Sawano T.","year":"1996","journal-title":"Biochem. Mol. Biol. Int."},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<120::AID-HUMU33>3.0.CO;2-8"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100380300005"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03772-3"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3892\/br.2023.1646"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098076"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11010007"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac109"},{"key":"e_1_2_9_35_1","first-page":"427","volume":"66","author":"Kodron A.","year":"2019","journal-title":"Acta Biochim. Pol."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.81"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1009792"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.8840"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy107"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2312"},{"key":"e_1_2_9_41_1","first-page":"4291","volume":"68","author":"Asciolla J. J.","year":"2012","journal-title":"J Vis Exp"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.9339"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01101"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-19243"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.03.189"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.1276508"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2008.05.087"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)49906-6"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.03.034"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00199-16"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100437"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1241"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)49906-6"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku466"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.08.005"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy107"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy354"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2015.05.010"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.739482"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0c00039"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03952-w"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702824200"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgz140"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051405"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9010083"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci12070952"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1080\/13510002.2022.2036507"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology8020031"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/164_2017_2"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2009.02.024"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920211794520150"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-9596"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.4137\/JCD.S11034"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.1c00130"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010physiol\u2010021317\u2010121427"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.598112"},{"key":"e_1_2_9_77_1","volume":"112","year":"2013","journal-title":"Circ. Res."},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.11-9109"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.4.967"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380060405"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.227202"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.70.1.190"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(96)64030-0"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0595-47"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa860"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz218"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000317"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab228"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0144273"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114650"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv498"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000530"},{"key":"e_1_2_9_93_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.014603"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202401856","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T21:33:16Z","timestamp":1759786396000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202401856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,12]]},"references-count":93,"journal-issue":{"issue":"41","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1002\/advs.202401856"],"URL":"https:\/\/doi.org\/10.1002\/advs.202401856","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,12]]},"assertion":[{"value":"2024-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2401856"}}