{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:39:29Z","timestamp":1776904769470,"version":"3.51.2"},"reference-count":55,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":22,"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":["82301006"],"award-info":[{"award-number":["82301006"]}],"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":["82271904"],"award-info":[{"award-number":["82271904"]}],"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":["82070914"],"award-info":[{"award-number":["82070914"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["21ZR1452700"],"award-info":[{"award-number":["21ZR1452700"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2703400"],"award-info":[{"award-number":["2022YFC2703400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>OXA1L is crucial for mitochondrial protein insertion and assembly into the inner mitochondrial membrane, and its variants have been recently linked to mitochondrial encephalopathy. However, the definitive pathogenic link between <jats:italic>OXA1L<\/jats:italic> variants and mitochondrial diseases as well as the underlying pathogenesis remains elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we identified bi\u2010allelic variants of c.620G&gt;T, p.(Cys207Phe) and c.1163_1164del, p.(Val388Alafs*15) in <jats:italic>OXA1L<\/jats:italic> gene in a mitochondrial myopathy patient using whole exome sequencing. To unravel the genotype\u2013phenotype relationship and underlying pathogenic mechanism between <jats:italic>OXA1L<\/jats:italic> variants and mitochondrial diseases, patient\u2010specific human\u2010induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into myotubes, while <jats:italic>OXA1L<\/jats:italic> knockout human immortalised skeletal muscle cells (IHSMC) and a conditional skeletal muscle knockout mouse model was generated using clustered regularly interspaced short palindromic repeats\/Cas9 genomic editing technology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both patient\u2010specific hiPSC differentiated myotubes and <jats:italic>OXA1L<\/jats:italic> knockout IHSMC showed combined mitochondrial respiratory chain defects and oxidative phosphorylation (OXPHOS) impairments. Notably, in <jats:italic>OXA1L<\/jats:italic>\u2010knockout IHSMC, transfection of wild\u2010type human OXA1L but not truncated mutant form rescued the respiratory chain defects. Moreover, skeletal muscle conditional <jats:italic>Oxa1l<\/jats:italic> knockout mice exhibited OXPHOS deficiencies and skeletal muscle morphofunctional abnormalities, recapitulating the phenotypes of mitochondrial myopathy. Further functional investigations revealed that impaired OXPHOS resulting of OXA1L deficiency led to elevated reactive oxygen species production, which possibly activated the nuclear factor kappa B signalling pathway, triggering cell apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Together, our findings reinforce the genotype\u2013phenotype association between <jats:italic>OXA1L<\/jats:italic> variations and mitochondrial diseases and further delineate the potential molecular mechanisms of how OXA1L deficiency causes skeletal muscle deficits in mitochondrial myopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Keypoints<\/jats:title><jats:p><jats:list>\n<jats:list-item><jats:p><jats:italic>OXA1L<\/jats:italic> gene bi\u2010allelic variants cause mitochondrial myopathy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>OXA1L deficiency results in combined mitochondrial respiratory chain defects and OXPHOS impairments.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>OXA1L deficiency leads to elevated ROS production, which may activate the NF\u2010\u03baB signalling pathway, disturbing myogenic gene expression and triggering cell apoptosis.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70385","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T06:55:02Z","timestamp":1750748102000},"source":"Crossref","is-referenced-by-count":4,"title":["OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway"],"prefix":"10.1002","volume":"15","author":[{"given":"Yongkun","family":"Zhan","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Center The Second Affiliated Hospital &amp; Yuying Children's Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanjie","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianlong","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaoting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiqian","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hezhi","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Center The Second Affiliated Hospital &amp; Yuying Children's Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"},{"name":"Department of Clinical Laboratory State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-0910","authenticated-orcid":false,"given":"Yongguo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center Shanghai Institute for Pediatric Research Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Department of Pediatric Endocrinology and Genetics Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010021\u201000415\u20100"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010019\u20100173\u20108"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571\u2010022\u201001302\u20108"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/b978\u20100\u201012\u2010802395\u20102.00010\u20109"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.051"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311\u2010018\u201000674\u20104"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.80"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11707"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(21)00098\u20103"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12104"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/b978\u20100\u201012\u2010821751\u20101.00011\u20107"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(18)30727\u2010x"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R115.638171"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.07.018"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe0763"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg624"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.5.2250"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.6.1281"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg623"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.09.044"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201809060"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u201061779\u2010504\u20106_4"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/2044\u20105040\u20102\u20108"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2022.04.008"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000244435.27645.54"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.177"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2634"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13065"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.001"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/9159101"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.178"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2021.0266"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010023\u201001433\u20106"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167330"},{"key":"e_1_2_12_36_1","doi-asserted-by":"crossref","unstructured":"Armirola\u2010RicaurteC MorantL AdantI et\u00a0al.Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.medRxiv.2024. doi:10.1101\/2024.07.03.24309787","DOI":"10.1101\/2024.07.03.24309787"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.02.014"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.954"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010023\u201000815\u2010w"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw176"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab426"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1042\/bcj20220233"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl061"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/982794"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102398"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19020417"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2017.08.008"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.07.005"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6842568"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0002\u20109440(10)63335\u20104"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2004.06.021"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5488.2363"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.02020\u201006"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1591672"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11602"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/593267"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70385","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T07:05:19Z","timestamp":1750835119000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.70385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":55,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/ctm2.70385"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.70385","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]},"article-number":"e70385"}}