{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:13:13Z","timestamp":1791267193881,"version":"4.1.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006662","name":"NIHR","doi-asserted-by":"publisher","award":["BRC-1215-20\u2009014"],"award-info":[{"award-number":["BRC-1215-20\u2009014"]}],"id":[{"id":"10.13039\/100006662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"National Institute of Health and Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000305","name":"National Eye Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000305","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clinician Scientist Fellowship Award","award":["G1002570"],"award-info":[{"award-number":["G1002570"]}]},{"name":"Advanced Fellowship Award","award":["NIHR301696"],"award-info":[{"award-number":["NIHR301696"]}]},{"DOI":"10.13039\/100002089","name":"Fight for Sight","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001116","name":"Foundation Fighting Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001116","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterized by the preferential loss of retinal ganglion cells (RGCs), resulting in optic nerve degeneration and progressive bilateral central vision loss. More than 60% of genetically confirmed patients with DOA carry variants in the nuclear OPA1 gene, which encodes for a ubiquitously expressed, mitochondrial GTPase protein. OPA1 has diverse functions within the mitochondrial network, facilitating inner membrane fusion and cristae modelling, regulating mitochondrial DNA maintenance and coordinating mitochondrial bioenergetics. There are currently no licensed disease-modifying therapies for DOA and the disease mechanisms driving RGC degeneration are poorly understood. Here, we describe the generation of isogenic, heterozygous OPA1 null induced pluripotent stem cell (iPSC) (OPA1+\/\u2212) through clustered regularly interspaced short palindromic repeats (CRISPR)\/Cas9 gene editing of a control cell line, in conjunction with the generation of DOA patient-derived iPSC carrying OPA1 variants, namely, the c.2708_2711delTTAG variant (DOA iPSC), and previously reported missense variant iPSC line (c.1334G&amp;gt;A, DOA plus [DOA]+ iPSC) and CRISPR\/Cas9 corrected controls. A two-dimensional (2D) differentiation protocol was used to study the effect of OPA1 variants on iPSC-RGC differentiation and mitochondrial function. OPA1+\/\u2212, DOA and DOA+ iPSC showed no differentiation deficit compared to control iPSC lines, exhibiting comparable expression of all relevant markers at each stage of differentiation. OPA1+\/\u2212 and OPA1 variant iPSC-RGCs exhibited impaired mitochondrial homeostasis, with reduced bioenergetic output and compromised mitochondrial DNA maintenance. These data highlight mitochondrial deficits associated with OPA1 dysfunction in human iPSC-RGCs, and establish a platform to study disease mechanisms that contribute to RGC loss in DOA, as well as potential therapeutic interventions.<\/jats:p>","DOI":"10.1093\/hmg\/ddac128","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T10:42:32Z","timestamp":1654166552000},"page":"3478-3493","source":"Crossref","is-referenced-by-count":25,"title":["Modelling autosomal dominant optic atrophy associated with <i>OPA1<\/i> variants in iPSC-derived retinal ganglion cells"],"prefix":"10.1093","volume":"31","author":[{"given":"Paul E","family":"Sladen","sequence":"first","affiliation":[{"name":"UCL Institute of Ophthalmology , 11-43 Bath Street, London EC1V 9EL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Jovanovic","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology , 11-43 Bath Street, London EC1V 9EL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosellina","family":"Guarascio","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology , 11-43 Bath Street, London EC1V 9EL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Ottaviani","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology , 11-43 Bath Street, London EC1V 9EL , UK"},{"name":"Department of Biology , University of Padua, and Veneto Institute of Molecular Medicine, Padua 35129 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Salsbury","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology , William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Novoselova","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology , William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Paul","family":"Chapple","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology , William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Yu-Wai-Man","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology , 11-43 Bath Street, London EC1V 9EL , UK"},{"name":"Moorfields Eye Hospital NHS Foundation Trust , London EC1V 2PD , UK"},{"name":"Cambridge Eye Unit , Addenbrooke\u2019s Hospital, Cambridge University Hospital, Cambridge CB2 0QQ , UK"},{"name":"Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit , Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6429-654X","authenticated-orcid":false,"given":"Michael E","family":"Cheetham","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology , 11-43 Bath Street, London EC1V 9EL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"2022101308102380000_ref1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1097\/WNO.0000000000001375","article-title":"Induced pluripotent stem cells for inherited optic neuropathies-disease modeling and therapeutic development","volume":"42","author":"Harvey","year":"2022","journal-title":"J. Neuroophthalmol."},{"key":"2022101308102380000_ref2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s00401-016-1625-2","article-title":"A neurodegenerative perspective on mitochondrial optic neuropathies","volume":"132","author":"Yu-Wai-Man","year":"2016","journal-title":"Acta. Neuropathol."},{"key":"2022101308102380000_ref3","first-page":"7","article-title":"Dominant optic atrophy","author":"Lenears","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"2022101308102380000_ref4","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1093\/brain\/awq007","article-title":"Multi-system neurological disease is common in patients with OPA1 mutations","volume":"133","author":"Yu-Wai-Man","year":"2010","journal-title":"Brain"},{"key":"2022101308102380000_ref5","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1016\/j.ophtha.2013.04.022","article-title":"Dominant optic atrophy\u2014Novel OPA1 mutations and revised prevalence estimates","volume":"120","author":"Yu-Wai-Man","year":"2013","journal-title":"Ophthalmology"},{"key":"2022101308102380000_ref6","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1186\/s13023-019-1187-1","article-title":"OPA1: 516 unique variants and 831 patients registered in an updated centralized Variome database","volume":"14","author":"Le Roux","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"2022101308102380000_ref7","doi-asserted-by":"crossref","first-page":"e0253987","DOI":"10.1371\/journal.pone.0253987","article-title":"Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants","volume":"16","author":"Weisschuh","year":"2021","journal-title":"PLoS One"},{"key":"2022101308102380000_ref8","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1136\/jmg.39.8.e47","article-title":"Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease","volume":"39","author":"Marchbank","year":"2002","journal-title":"J. Med. Genet."},{"key":"2022101308102380000_ref9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1136\/jmg.2008.062570","article-title":"Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy","volume":"46","author":"Fuhrmann","year":"2009","journal-title":"J. Med. Genet."},{"key":"2022101308102380000_ref10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/79944","article-title":"OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28","volume":"26","author":"Alexander","year":"2000","journal-title":"Nat. Genet."},{"key":"2022101308102380000_ref11","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1083\/jcb.200704110","article-title":"OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L","volume":"178","author":"Song","year":"2007","journal-title":"J. Cell Biol."},{"key":"2022101308102380000_ref12","doi-asserted-by":"crossref","first-page":"7743","DOI":"10.1074\/jbc.C200677200","article-title":"Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis","volume":"278","author":"Olichon","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2022101308102380000_ref13","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1093\/hmg\/ddm079","article-title":"OPA1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function","volume":"16","author":"Davies","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2022101308102380000_ref14","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1002\/ana.20681","article-title":"OPA1 R445H mutation in optic atrophy associated with sensorineural deafness","volume":"58","author":"Amati-Bonneau","year":"2005","journal-title":"Ann. Neurol."},{"key":"2022101308102380000_ref15","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1093\/brain\/awm335","article-title":"OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion","volume":"131","author":"Zanna","year":"2008","journal-title":"Brain"},{"key":"2022101308102380000_ref16","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1093\/brain\/awm005","article-title":"A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy","volume":"130","author":"Alavi","year":"2007","journal-title":"Brain"},{"key":"2022101308102380000_ref17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/diseases5010001","article-title":"Mitochondrial dynamics in mitochondrial diseases","volume":"5","author":"Su\u00e1rez-Rivero","year":"2017","journal-title":"Diseases"},{"key":"2022101308102380000_ref18","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.15252\/embj.201488349","article-title":"OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand","volume":"33","author":"Patten","year":"2014","journal-title":"EMBO J."},{"key":"2022101308102380000_ref19","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/cdd.2012.128","article-title":"Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity","volume":"20","author":"Kushnareva","year":"2013","journal-title":"Cell Death Differ."},{"key":"2022101308102380000_ref20","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1016\/j.celrep.2017.05.073","article-title":"OPA1 isoforms in the hierarchical organization of mitochondrial functions","volume":"19","author":"Del Dotto","year":"2017","journal-title":"Cell Rep."},{"key":"2022101308102380000_ref21","doi-asserted-by":"crossref","first-page":"180","DOI":"10.3389\/fcell.2020.00180","article-title":"OPA1-Exon4b binds to mtDNA D-loop for transcriptional and metabolic modulation, independent of mitochondrial fusion","volume":"8","author":"Yang","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2022101308102380000_ref22","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1212\/01.WNL.0000157282.76715.B1","article-title":"Mitochondrial DNA content is decreased in autosomal dominant optic atrophy","volume":"64","author":"Kim","year":"2004","journal-title":"Neurology"},{"key":"2022101308102380000_ref23","doi-asserted-by":"crossref","first-page":"e003012","DOI":"10.1161\/JAHA.112.003012","article-title":"OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability","volume":"1","author":"Chen","year":"2012","journal-title":"J. Am. Heart Assoc."},{"key":"2022101308102380000_ref24","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1093\/brain\/awm298","article-title":"OPA1 mutations induce mitochondrial DNA instability and optic atrophy \u2018plus\u2019 phenotypes","volume":"131","author":"Amati-Bonneau","year":"2008","journal-title":"Brain"},{"key":"2022101308102380000_ref25","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1093\/hmg\/ddq209","article-title":"OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules","volume":"19","author":"Yu-Wai-Man","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2022101308102380000_ref26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1093\/brain\/awm272","article-title":"Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance","volume":"131","author":"Hudson","year":"2008","journal-title":"Brain"},{"key":"2022101308102380000_ref27","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1212\/WNL.0000000000003491","article-title":"Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations","volume":"88","author":"Liao","year":"2017","journal-title":"Neurology"},{"key":"2022101308102380000_ref28","doi-asserted-by":"crossref","first-page":"101154","DOI":"10.1016\/j.isci.2020.101154","article-title":"Optic atrophy 1 controls human neuronal development by preventing aberrant nuclear DNA methylation","volume":"23","author":"Caglayan","year":"2020","journal-title":"iScience"},{"key":"2022101308102380000_ref29","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.omtn.2021.08.015","article-title":"CRISPR-Cas9 correction of OPA1 c.1334G&gt;A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs","volume":"26","author":"Sladen","year":"2021","journal-title":"Mol. Ther-Nucl. Acids."},{"key":"2022101308102380000_ref30","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.scr.2016.03.011","article-title":"Generation of a human iPSC line from a patient with an optic atrophy \u2018plus\u2019 phenotype due to a mutation in the OPA1 gene","volume":"16","author":"Galera-Monge","year":"2016","journal-title":"Stem Cell Res."},{"key":"2022101308102380000_ref31","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.scr.2017.08.017","article-title":"Establishment of a human DOA 'plus' iPSC line, IISHDOi003-A, with the mutation in the OPA1 gene: c.1635C&gt;A; p.Ser545Arg","volume":"24","author":"Zurita-D\u00edaz","year":"2017","journal-title":"Stem Cell Res."},{"key":"2022101308102380000_ref32","doi-asserted-by":"crossref","first-page":"102278","DOI":"10.1016\/j.scr.2021.102278","article-title":"Generation of an induced pluripotent stem cell line BIOi002-A from a patient with autosomal dominant optic atrophy","volume":"53","author":"Zhang","year":"2021","journal-title":"Stem Cell Res."},{"key":"2022101308102380000_ref33","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":"2022101308102380000_ref34","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1016\/j.ophtha.2009.12.038","article-title":"The prevalence and natural history of dominant optic atrophy due to OPA1 mutations","volume":"117","author":"Yu-Wai-Man","year":"2010","journal-title":"Ophthalmology"},{"key":"2022101308102380000_ref35","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1002\/sctm.17-0059","article-title":"Enhanced stem cell differentiation and immunopurification of genome engineered human retinal ganglion cells","volume":"6","author":"Sluch","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"2022101308102380000_ref36","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1242\/dev.128.13.2497","article-title":"Math5 is required for retinal ganglion cell and optic nerve formation","volume":"128","author":"Brown","year":"2001","journal-title":"Development"},{"key":"2022101308102380000_ref37","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ydbio.2008.01.015","article-title":"Near complete loss of retinal ganglion cells in the math5\/brn3b double knockout elicits severe reductions of other cell types during retinal development","volume":"316","author":"Moshiri","year":"2008","journal-title":"Dev. Biol."},{"key":"2022101308102380000_ref38","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1242\/dev.010751","article-title":"ISL1 and BRN3B co-regulate the differentiation of murine retinal ganglion cells","volume":"135","author":"Pan","year":"2008","journal-title":"Development"},{"key":"2022101308102380000_ref39","doi-asserted-by":"crossref","first-page":"E1559","DOI":"10.1073\/pnas.1421535112","article-title":"Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate","volume":"112","author":"Wu","year":"2015","journal-title":"PNAS"},{"key":"2022101308102380000_ref40","first-page":"1540","article-title":"\u03b3-Synuclein as a marker of retinal ganglion cells","volume":"14","author":"Surgucheva","year":"2008","journal-title":"Mol. Vis."},{"key":"2022101308102380000_ref41","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1002\/acn3.305","article-title":"Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis","volume":"3","author":"Millet","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2022101308102380000_ref42","doi-asserted-by":"crossref","first-page":"7753","DOI":"10.1093\/nar\/gkt567","article-title":"LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1","volume":"41","author":"Hou","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2022101308102380000_ref43","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.stem.2010.04.017","article-title":"Pax6 is a human neuroectoderm cell fate determinant","volume":"7","author":"Zhang","year":"2010","journal-title":"Cell Stem Cell"},{"key":"2022101308102380000_ref44","doi-asserted-by":"crossref","first-page":"30552","DOI":"10.1038\/srep30552","article-title":"Enriched retinal ganglion cells derived from human embryonic stem cells","volume":"6","author":"Gill","year":"2016","journal-title":"Sci. Rep."},{"key":"2022101308102380000_ref45","first-page":"536","article-title":"Stage-specific differentiation of iPSCs toward retinal ganglion cell lineage","volume":"22","author":"Deng","year":"2016","journal-title":"Mol. Vis."},{"key":"2022101308102380000_ref46","doi-asserted-by":"crossref","first-page":"5155","DOI":"10.1242\/dev.00723","article-title":"Specification of the vertebrate eye by a network of eye field transcription factors","volume":"130","author":"Zuber","year":"2003","journal-title":"Development"},{"key":"2022101308102380000_ref47","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1002\/stem.167","article-title":"Noggin elicits retinal fate in Xenopus animal cap embryonic stem cells","volume":"27","author":"Lan","year":"2009","journal-title":"Stem Cells"},{"key":"2022101308102380000_ref48","doi-asserted-by":"crossref","first-page":"4417","DOI":"10.1007\/s00018-021-03814-w","article-title":"Genetic control of retinal ganglion cell genesis","volume":"78","author":"Lyu","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"2022101308102380000_ref49","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/ana.25221","article-title":"Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1","volume":"83","author":"Jonikas","year":"2018","journal-title":"Ann. Neurol."},{"key":"2022101308102380000_ref50","doi-asserted-by":"crossref","first-page":"4646","DOI":"10.1016\/j.celrep.2019.11.111","article-title":"Reconstitution of the human Nigro-striatal pathway on-a-chip reveals OPA1-dependent mitochondrial defects and loss of dopaminergic synapses","volume":"29","author":"Iannielli","year":"2019","journal-title":"Cell Rep."},{"key":"2022101308102380000_ref51","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1016\/j.celrep.2018.01.089","article-title":"Pharmacological inhibition of Necroptosis protects from dopaminergic neuronal cell death in Parkinson\u2019s disease models","volume":"22","author":"Iannielli","year":"2018","journal-title":"Cell Rep."},{"key":"2022101308102380000_ref52","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.mito.2017.08.014","article-title":"Mitochondrial dynamics, transport, and quality control: A bottleneck for retinal ganglion cell viability in optic neuropathies","volume":"36","author":"Ito","year":"2017","journal-title":"Mitochondrion"},{"key":"2022101308102380000_ref53","doi-asserted-by":"crossref","first-page":"e13374","DOI":"10.7554\/eLife.13374","article-title":"Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation","volume":"5","author":"Zheng","year":"2016","journal-title":"Elife"},{"key":"2022101308102380000_ref54","first-page":"37","article-title":"Mitochondrial dysfunction and multiple sclerosis","volume":"8","author":"Barcelos","year":"2019","journal-title":"Biology (Basel)."},{"key":"2022101308102380000_ref55","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/ana.410300304","article-title":"Mitochondrial oxidative phosphorylation defects in parkinson's disease","volume":"30","author":"Wallace","year":"1991","journal-title":"Ann. Neurol."},{"key":"2022101308102380000_ref56","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.pediatrneurol.2008.07.013","article-title":"Leigh and Leigh-like syndrome in children and adults","volume":"39","author":"Finsterer","year":"2008","journal-title":"Pediatr. Neurol."},{"key":"2022101308102380000_ref57","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2147\/EB.S9078","article-title":"Energy metabolism of the visual system","volume":"2","author":"Wong-Riley","year":"2010","journal-title":"Eye Brain."},{"key":"2022101308102380000_ref58","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mito.2016.10.002","article-title":"Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G&gt;A and m.14484T&gt;C of the mitochondrial DNA","volume":"36","author":"Catarino","year":"2017","journal-title":"Mitochondrion"},{"key":"2022101308102380000_ref59","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1167\/iovs.12-9596","article-title":"Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts","volume":"53","author":"Lee","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2022101308102380000_ref60","doi-asserted-by":"crossref","first-page":"e0140919","DOI":"10.1371\/journal.pone.0140919","article-title":"Measurement of systemic mitochondrial function in advanced primary open-angle glaucoma and Leber hereditary optic neuropathy","volume":"10","author":"Van Bergen","year":"2015","journal-title":"PLoS One"},{"key":"2022101308102380000_ref61","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1136\/jmg.39.3.162","article-title":"Leber hereditary optic neuropathy","volume":"39","author":"Yu-Wai-Man","year":"2002","journal-title":"J. Med. Genet."},{"key":"2022101308102380000_ref62","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1101\/gr.108696.110","article-title":"OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution","volume":"21","author":"Elachouri","year":"2011","journal-title":"Genome Res."},{"key":"2022101308102380000_ref63","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/hmg\/dds435","article-title":"Universal heteroplasmy of human mitochondrial DNA","volume":"22","author":"Payne","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2022101308102380000_ref64","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/ng1769","article-title":"High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease","volume":"38","author":"Bender","year":"2006","journal-title":"Nat. Genet."},{"key":"2022101308102380000_ref65","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/labinvest.3780140","article-title":"Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease","volume":"80","author":"Monte","year":"2000","journal-title":"Lab. Investig."},{"key":"2022101308102380000_ref66","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.nbd.2013.10.013","article-title":"LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction","volume":"62","author":"Sanders","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"2022101308102380000_ref67","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nprot.2018.007","article-title":"Simultaneous reprogramming and gene editing of human fibroblasts","volume":"13","author":"Howden","year":"2018","journal-title":"Nat. Protoc."},{"key":"2022101308102380000_ref68","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat. Protoc."},{"key":"2022101308102380000_ref69","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nmeth.1591","article-title":"A more efficient method to generate integration-free human iPS cells","volume":"8","author":"Okita","year":"2011","journal-title":"Nat. Methods"},{"key":"2022101308102380000_ref70","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13062-015-0035-z","article-title":"\"Off-Spotter\": very fast and exhaustive enumeration of genomic lookalikes for designing CRISPR\/Cas guide RNAs","volume":"10","author":"Pliatsika","year":"2015","journal-title":"Biol. Direct"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac128\/44385835\/ddac128.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/20\/3478\/46416822\/ddac128.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/20\/3478\/46416822\/ddac128.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T08:14:18Z","timestamp":1665648858000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/20\/3478\/6597093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,2]]},"references-count":70,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,6,2]]},"published-print":{"date-parts":[[2022,10,10]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac128","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,10,15]]},"published":{"date-parts":[[2022,6,2]]}}}