{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T22:34:46Z","timestamp":1792276486157,"version":"4.4.0"},"reference-count":195,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,25]],"date-time":"2021-12-25T00:00:00Z","timestamp":1640390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns\u2013Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion\/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.<\/jats:p>","DOI":"10.3390\/ijms23010210","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T01:00:54Z","timestamp":1640566854000},"page":"210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Mitochondrial Retinopathies"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9067-5508","authenticated-orcid":false,"given":"Massimo","family":"Zeviani","sequence":"first","affiliation":[{"name":"Department of Neurosciences, The Clinical School, University of Padova, 35128 Padova, Italy"},{"name":"Veneto Institute of Molecular Medicine, Via Orus 2, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-6404","authenticated-orcid":false,"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna, 40139 Bologna, Italy"},{"name":"Programma di Neurogenetica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Via Altura 6, 40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1101\/sqb.2009.74.031","article-title":"Mitochondria, bioenergetics, and the epigenome in eukaryotic and human evolution","volume":"74","author":"Wallace","year":"2009","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1146\/annurev.genet.39.110304.095751","article-title":"A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine","volume":"39","author":"Wallace","year":"2005","journal-title":"Annu. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33232","DOI":"10.1074\/jbc.M802404200","article-title":"Control over the contribution of the mitochondrial membrane potential (\u0394\u03a8) and proton gradient (\u0394pH) to the protonmotive force (\u0394p)","volume":"283","author":"Dzbek","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1016\/j.bbabio.2011.09.018","article-title":"Chemiosmotic coupling in oxidative and photosynthetic phosphorylation (1966)","volume":"1807","author":"Mitchell","year":"2011","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_5","first-page":"667","article-title":"Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling","volume":"29","author":"Garlid","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jmb.2019.06.032","article-title":"Outstanding Questions in Mitophagy: What We Do and Do Not Know","volume":"432","author":"Ganley","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-genom-082509-141720","article-title":"The mitochondrial proteome and human disease","volume":"11","author":"Calvo","year":"2010","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1146\/annurev.biochem.76.081205.150955","article-title":"Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine","volume":"76","author":"Wallace","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16080","DOI":"10.1038\/nrdp.2016.80","article-title":"Mitochondrial diseases","volume":"2","author":"Gorman","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1093\/brain\/awh259","article-title":"Mitochondrial disorders","volume":"127","author":"Zeviani","year":"2004","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nrneurol.2013.126","article-title":"The clinical maze of mitochondrial neurology","volume":"9","author":"DiMauro","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1056\/NEJMra022567","article-title":"Mitochondrial respiratory\u2212chain diseases","volume":"348","author":"DiMauro","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/9780470725207.ch15","article-title":"Mitochondrial mutations: Genotype to phenotype","volume":"287","author":"Schon","year":"2007","journal-title":"Novartis Found. Symp."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S1474-4422(10)70116-2","article-title":"A neurological perspective on mitochondrial disease","volume":"9","author":"McFarland","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"DiMauro, S., Hirano, M., and Schon, E. (2006). Mitochondrial ophthalmology. Mitochondrial Medicine, Informa Healthcare.","DOI":"10.1201\/b14623"},{"key":"ref_16","unstructured":"Miller, N.R., Newman, N.J., Biousse, V., and Kerrison, J.B. (2005). Walsh & Hoyt\u2019s Clinical Neuro-Ophthalmology, Lippincott Williams & Wilkins. [6th ed.]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/B978-0-12-819975-6.00020-0","article-title":"Retina and melanopsin neurons","volume":"179","author":"Carelli","year":"2021","journal-title":"Handb. Clin. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/0042-6989(83)90107-4","article-title":"Three light-evoked responses of the retinal pigment epithelium","volume":"23","author":"Steinberg","year":"1983","journal-title":"Vis. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1073\/pnas.93.2.560","article-title":"How photons start vision","volume":"93","author":"Baylor","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e28899","DOI":"10.7554\/eLife.28899","article-title":"Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye","volume":"6","author":"Kanow","year":"2017","journal-title":"eLife"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1001\/archopht.1964.00970020794009","article-title":"Retinal oxygen utilization measured by hyperbaric blackout","volume":"72","author":"Anderson","year":"1964","journal-title":"Arch. Ophthalmol."},{"key":"ref_23","first-page":"1922","article-title":"Intraretinal oxygen consumption in the rat in vivo","volume":"43","author":"Cringle","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1085\/jgp.77.6.667","article-title":"Glycolytic and oxidative metabolism in relation to retinal function","volume":"77","author":"Winkler","year":"1981","journal-title":"J. Gen. Physiol."},{"key":"ref_25","first-page":"48","article-title":"Glucose metabolism in cat outer retina. Effects of light and hyperoxia","volume":"38","author":"Wang","year":"1997","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e25946","DOI":"10.7554\/eLife.25946","article-title":"Glycolytic reliance promotes anabolism in photoreceptors","volume":"6","author":"Chinchore","year":"2017","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/ceo.12952","article-title":"Glucose metabolism in mammalian photoreceptor inner and outer segments","volume":"45","author":"Narayan","year":"2017","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1016\/j.celrep.2018.04.111","article-title":"Aerobic glycolysis is essential for normal rod function and controls secondary cone death in retinitis pigmentosa","volume":"23","author":"Petit","year":"2018","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.preteyeres.2003.10.003","article-title":"Mitochondrial dysfunction as a cause of optic neuropathies","volume":"23","author":"Carelli","year":"2004","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.preteyeres.2010.11.002","article-title":"Mitochondrial optic neuropathies\u2014Disease mechanisms and therapeutic strategies","volume":"30","author":"Griffiths","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100935","DOI":"10.1016\/j.preteyeres.2020.100935","article-title":"Dominant optic atrophy: Culprit mitochondria in the optic nerve","volume":"83","author":"Lenaers","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1167\/iovs.12-10452","article-title":"Mathematically modelling the involvement of axons in Leber\u2019s hereditary optic neuropathy","volume":"53","author":"Pan","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1523\/JNEUROSCI.12-03-00840.1992","article-title":"Energy metabolism of rabbit retina as related to function: High cost of Na+ transport","volume":"12","author":"Ames","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Niven, J.E., Anderson, J.C., and Laughlin, S.B. (2007). Fly photoreceptors demonstrate energy-information trade-offs in neural coding. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050116"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.cub.2008.10.029","article-title":"ATP consumption by mammalian rod photoreceptors in darkness and in light","volume":"18","author":"Okawa","year":"2008","journal-title":"Curr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nn.2234","article-title":"Stimulation of the insulin\/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa","volume":"12","author":"Punzo","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.cell.2015.03.023","article-title":"Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis","volume":"161","author":"Fridlich","year":"2015","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1111\/aos.13141","article-title":"A review of the mechanisms of cone degeneration in retinitis pigmentosa","volume":"94","author":"Narayan","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.celrep.2016.03.022","article-title":"Two-step reactivation of dormant cones in retinitis pigmentosa","volume":"15","author":"Wang","year":"2016","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1016\/j.ophtha.2013.12.011","article-title":"Glucose-induced temporary visual recovery in primary open-angle glaucoma: A double-blind, randomized study","volume":"121","author":"Casson","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/ceo.12581","article-title":"Effect of subconjunctival glucose on retinal ganglion cell survival in experimental retinal ischaemia and contrast sensitivity in human glaucoma","volume":"44","author":"Shibeeb","year":"2016","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_42","first-page":"428","article-title":"A new mitochondrial disease associated with mitochondrial DNA heteroplasmy","volume":"46","author":"Holt","year":"1990","journal-title":"Am. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1136\/jnnp.63.1.16","article-title":"Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: A clinical, biochemical, and molecular study in six families","volume":"63","author":"Uziel","year":"1997","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_44","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, E., Bean, L.J.H., Gripp, K.W., Mirzaa, G.M., and Amemiya, A. (2021, December 20). Mitochondrial DNA-Associated Leigh Syndrome and NARP. 2003 Oct 30 [Updated 2017 Sep 28], GeneReviews\u00ae [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1173\/."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23519","DOI":"10.1073\/pnas.2013998117","article-title":"Structure of the dimeric ATP synthase from bovine mitochondria","volume":"117","author":"Spikes","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/8904_2014_332","article-title":"m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening","volume":"17","author":"Mori","year":"2014","journal-title":"JIMD Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1212\/WNL.51.6.1525-a","article-title":"Deletions of mitochondrial DNA in Kearns-Sayre syndrome","volume":"51","author":"Zeviani","year":"1998","journal-title":"Neurology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/S0140-6736(89)91256-7","article-title":"Duplications of mitochondrial DNA in mitochondrial myopathy","volume":"1","author":"Poulton","year":"1989","journal-title":"Lancet"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9509","DOI":"10.1073\/pnas.86.23.9509","article-title":"Detection of \u201cdeleted\u201d mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome","volume":"86","author":"Mita","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","first-page":"1119","article-title":"Mitochondrial disorders: Analysis of their clinical and imaging characteristics","volume":"14","author":"Barkovich","year":"1993","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7952","DOI":"10.1073\/pnas.86.20.7952","article-title":"Spontaneous Kearns-Sayre\/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: A slip-replication model and metabolic therapy","volume":"86","author":"Shoffner","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1172\/JCI114881","article-title":"Pearson\u2019s marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy","volume":"86","author":"Cormier","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1086\/342482","article-title":"Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with pearson syndrome","volume":"71","author":"Shanske","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1126\/science.2711184","article-title":"A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA","volume":"244","author":"Schon","year":"1989","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S1357-4310(00)01805-0","article-title":"Mitochondrial DNA mutations in the pathogenesis of human disease","volume":"6","author":"Chinnery","year":"2000","journal-title":"Mol. Med. Today"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10614","DOI":"10.1073\/pnas.88.23.10614","article-title":"Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction","volume":"88","author":"Hayashi","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1172\/JCI117061","article-title":"Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy","volume":"93","author":"Mariotti","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Birtel, J., von Landenberg, C., Gliem, M., Gliem, C., Reimann, J., Kunz, W.S., Herrmann, P., Betz, C., Caswell, R., and Nesbitt, V. (2021). Mitochondrial Retinopathy. Ophthalmol. Retin.","DOI":"10.1016\/j.oret.2021.02.017"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1080\/07853890600946724","article-title":"Age-related macular degeneration\u2014Emerging pathogenetic and therapeutic concepts","volume":"38","author":"Gehrs","year":"2006","journal-title":"Ann. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7304","DOI":"10.1523\/JNEUROSCI.0190-15.2015","article-title":"Investigating mitochondria as a target for treating age-related macular degeneration","volume":"35","author":"Terluk","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101201","DOI":"10.1016\/j.redox.2019.101201","article-title":"Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors","volume":"24","author":"Brown","year":"2019","journal-title":"Redox Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"AMD41","DOI":"10.1167\/iovs.18-24289","article-title":"Perspective on AMD pathobiology: A bioenergetic crisis in the RPE","volume":"59","author":"Fisher","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0014-4835(03)00023-X","article-title":"Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: A possible mechanism for RPE aging and age-related macular degeneration","volume":"76","author":"Liang","year":"2003","journal-title":"Exp. Eye Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.neurobiolaging.2005.05.012","article-title":"Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration","volume":"27","author":"Feher","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5470","DOI":"10.1167\/iovs.10-5429","article-title":"Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration","volume":"51","author":"Karunadharma","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1167\/iovs.10-6163","article-title":"Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration","volume":"52","author":"Lin","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1089\/biores.2015.0022","article-title":"Reactive oxygen species and mitochondrial DNA damage and repair in BCR-ABL1 cells resistant to Imatinib","volume":"4","author":"Blasiak","year":"2015","journal-title":"Biores. Open Access."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1093\/nar\/gkp100","article-title":"Oxidative stress induces degradation of mitochondrial DNA","volume":"37","author":"Shokolenko","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/1873-3468.12956","article-title":"Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease","volume":"592","author":"Nissanka","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Kaarniranta, K., Pawlowska, E., Szczepanska, J., Jablkowska, A., and Blasiak, J. (2019). Role of mitochondrial DNA damage in ROS-mediated pathogenesis of age-related macular degeneration (AMD). Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102374"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"R139","DOI":"10.1093\/hmg\/ddx273","article-title":"Optic neuropathies: The tip of the neurodegeneration iceberg","volume":"26","author":"Carelli","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.3201231","article-title":"Mitochondrial DNA mutation associated with Leber\u2019s hereditary optic neuropathy","volume":"242","author":"Wallace","year":"1988","journal-title":"Science"},{"key":"ref_73","first-page":"348","article-title":"Leber\u2019s optic atrophy, a possible example of maternal inheritance","volume":"24","author":"Erickson","year":"1972","journal-title":"Am. J. Hum. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Achilli, A., Iommarini, L., Olivieri, A., Pala, M., Hooshiar Kashani, B., Reynier, P., La Morgia, C., Valentino, M.L., Liguori, R., and Pizza, F. (2012). Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber\u2019s hereditary optic neuropathy. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042242"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1136\/jmedgenet-2016-104212","article-title":"Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy","volume":"54","author":"Gerber","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e138267","DOI":"10.1172\/JCI138267","article-title":"Impaired complex I repair causes recessive Leber\u2019s hereditary optic neuropathy","volume":"131","author":"Stenton","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_77","first-page":"249","article-title":"Uber hereditare und congenital-angelegte Sehnervenleiden","volume":"17","author":"Leber","year":"1871","journal-title":"Arch. Ophthalmol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1086\/346066","article-title":"The epidemiology of Leber hereditary optic neuropathy in the North East of England","volume":"72","author":"Griffiths","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"461","DOI":"10.5301\/ejo.5000055","article-title":"Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe","volume":"22","author":"Mascialino","year":"2012","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1097\/WNO.0000000000000570","article-title":"International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy","volume":"37","author":"Carelli","year":"2017","journal-title":"J. Neuroophthalmol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1001\/archopht.1982.01030040575003","article-title":"Ophthalmoscopic findings in Leber\u2019s hereditary optic neuropathy. I. Fundus findings in asymptomatic family members","volume":"100","author":"Nikoskelainen","year":"1982","journal-title":"Arch. Ophthalmol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ophtha.2004.09.033","article-title":"Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber\u2019s hereditary optic neuropathy mutations","volume":"112","author":"Savini","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1111\/ceo.13326","article-title":"Peripapillary vessel density changes in Leber\u2019s hereditary optic neuropathy: A new biomarker","volume":"46","author":"Balducci","year":"2018","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1001\/archopht.1983.01040020061011","article-title":"Ophthalmoscopic findings in Leber\u2019s hereditary optic neuropathy. II. The fundus findings in the affected family members","volume":"101","author":"Nikoskelainen","year":"1983","journal-title":"Arch. Ophthalmol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.ophtha.2009.07.026","article-title":"Natural history of Leber\u2019s hereditary optic neuropathy: Longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography","volume":"117","author":"Barboni","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.ophtha.2017.01.002","article-title":"Natural History of Conversion of Leber\u2019s Hereditary Optic Neuropathy: A Prospective Case Series","volume":"124","author":"Hwang","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1097\/WNO.0000000000001045","article-title":"Visual Outcomes in Leber Hereditary Optic Neuropathy Patients With the m.11778G>A (MTND4) Mitochondrial DNA Mutation","volume":"40","author":"Newman","year":"2020","journal-title":"J. Neuroophthalmol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1167\/iovs.06-0520","article-title":"Leber\u2019s hereditary optic neuropathy with childhood onset","volume":"47","author":"Barboni","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1136\/bjophthalmol-2016-310072","article-title":"Childhood-onset Leber hereditary optic neuropathy","volume":"101","author":"Majander","year":"2017","journal-title":"Br. J. Ophthalmol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s13023-014-0158-9","article-title":"Leber\u2019s hereditary optic neuropathy with late disease onset: Clinical and molecular characteristics of 20 patients","volume":"9","author":"Dimitriadis","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/WNO.0b013e3181772db4","article-title":"Leber hereditary optic neuropathy presenting in a 75-year-old man","volume":"28","author":"Bateman","year":"2008","journal-title":"J. Neuroophthalmol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.mito.2017.07.004","article-title":"Incomplete penetrance in mitochondrial optic neuropathies","volume":"36","author":"Caporali","year":"2017","journal-title":"Mitochondrion"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1086\/501236","article-title":"Haplogroup effects and recombination of mitochondrial DNA: Novel clues from the analysis of Leber hereditary optic neuropathy pedigrees","volume":"78","author":"Carelli","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1086\/519394","article-title":"Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background","volume":"81","author":"Hudson","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_95","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\u2019s hereditary optic neuropathy-associated mitochondrial DNA mutation","volume":"25","author":"Jiang","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1172\/JCI134965","article-title":"PRICKLE3 linked to ATPase biogenesis manifested Leber\u2019s hereditary optic neuropathy","volume":"130","author":"Yu","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1086\/498176","article-title":"Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder","volume":"77","author":"Hudson","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1080\/13816810701867607","article-title":"Evidence for a novel x-linked modifier locus for leber hereditary optic neuropathy","volume":"29","author":"Shankar","year":"2008","journal-title":"Ophthalmic Genet."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.ajo.2003.08.010","article-title":"Ophthalmologic findings in a large pedigree of 11778\/Haplogroup J Leber hereditary optic neuropathy","volume":"137","author":"Sadun","year":"2004","journal-title":"Am. J. Ophthalmol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1093\/brain\/awp158","article-title":"Gene-environment interactions in Leber hereditary optic neuropathy","volume":"132","author":"Kirkman","year":"2009","journal-title":"Brain"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1093\/brain\/awv339","article-title":"Parsing the differences in affected with LHON: Genetic versus environmental triggers of disease conversion","volume":"139","author":"Carelli","year":"2016","journal-title":"Brain"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1001\/archneur.62.5.730","article-title":"Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids","volume":"62","author":"Baracca","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1111\/j.1742-4658.2004.04542.x","article-title":"Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber\u2019s hereditary optic neuropathy","volume":"272","author":"Floreani","year":"2005","journal-title":"FEBS J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5810","DOI":"10.1074\/jbc.M110119200","article-title":"Cells bearing mutations causing Leber\u2019s hereditary optic neuropathy are sensitized to Fas-Induced apoptosis","volume":"277","author":"Danielson","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s10495-005-0742-5","article-title":"Caspase-independent death of Leber\u2019s hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G","volume":"10","author":"Zanna","year":"2005","journal-title":"Apoptosis"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1093\/brain\/awq276","article-title":"Oestrogens ameliorate mitochondrial dysfunction in Leber\u2019s hereditary optic neuropathy","volume":"134","author":"Giordano","year":"2011","journal-title":"Brain"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/brain\/awt343","article-title":"Efficient mitochondrial biogenesis drives incomplete penetrance in Leber\u2019s hereditary optic neuropathy","volume":"137","author":"Giordano","year":"2014","journal-title":"Brain"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e2021","DOI":"10.1038\/cddis.2015.364","article-title":"Cigarette toxicity triggers Leber\u2019s hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways","volume":"6","author":"Giordano","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_109","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":"ref_110","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/79936","article-title":"Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy","volume":"26","author":"Delettre","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/ana.25723","article-title":"ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy","volume":"88","author":"Caporali","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1212\/NXG.0000000000000428","article-title":"Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy","volume":"6","author":"Charif","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"fcab063","DOI":"10.1093\/braincomms\/fcab063","article-title":"Dominant ACO2 mutations are a frequent cause of isolated optic atrophy","volume":"3","author":"Charif","year":"2021","journal-title":"Brain Commun."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e110","DOI":"10.1136\/jmg.2003.016576","article-title":"OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract","volume":"41","author":"Reynier","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_115","first-page":"435","article-title":"Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene","volume":"43","author":"Reynier","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1093\/brain\/awx219","article-title":"Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission","volume":"140","author":"Gerber","year":"2017","journal-title":"Brain"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/ana.25550","article-title":"SSBP1 mutations in dominant optic atrophy with variable retinal degeneration","volume":"86","author":"Jurkute","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_118","first-page":"108","article-title":"SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder","volume":"130","author":"Ullah","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_119","first-page":"143","article-title":"Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy","volume":"130","author":"Sarzi","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_120","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":"Gerber","year":"2008","journal-title":"Brain"},{"key":"ref_121","first-page":"1","article-title":"Infantile optic atrophy with dominant mode of inheritance: A clinical and genetic study of 19 Danish families","volume":"164","author":"Kjier","year":"1959","journal-title":"Acta Ophthalmol. Suppl."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3892\/mmr.2016.5209","article-title":"Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1","volume":"14","author":"Lee","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1136\/jnnp.59.2.160","article-title":"Leber\u2019s \u201cplus\u201d: Neurological abnormalities in patients with Leber\u2019s hereditary optic neuropathy","volume":"59","author":"Nikoskelainen","year":"1995","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_124","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":"Griffiths","year":"2010","journal-title":"Brain"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0022-510X(96)00165-7","article-title":"Hereditary cerebellar ataxia with Leber\u2019s hereditary optic neuropathy mitochondrial DNA 11778 mutation","volume":"142","author":"Murakami","year":"1996","journal-title":"J. Neurol. Sci."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1212\/01.wnl.0000295505.74234.d0","article-title":"Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus","volume":"70","author":"Achilli","year":"2008","journal-title":"Neurology"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/8904_2017_79","article-title":"Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis","volume":"42","author":"Bursle","year":"2018","journal-title":"JIMD Rep."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00415-019-09619-z","article-title":"Leber hereditary optic neuropathy plus dystonia, and transverse myelitis due to double mutations in MT-ND4 and MT-ND6","volume":"267","author":"Berardo","year":"2020","journal-title":"J. Neurol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/WNO.0b013e3181fab1b4","article-title":"Axonal degeneration in peripheral nerves in a case of Leber hereditary optic neuropathy","volume":"31","author":"Mnatsakanyan","year":"2011","journal-title":"J. Neuroophthalmol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1212\/01.wnl.0000307668.75233.35","article-title":"Myelin, mitochondria, and autoimmunity: What\u2019s the connection?","volume":"70","author":"Carelli","year":"2008","journal-title":"Neurology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"132932","DOI":"10.1016\/j.neulet.2017.06.051","article-title":"Mitochondria in neuroinflammation\u2014Multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS","volume":"710","author":"Bargiela","year":"2019","journal-title":"Neurosci Lett."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1212\/01.wnl.0000437308.22603.43","article-title":"Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations","volume":"81","author":"Pfeffer","year":"2013","journal-title":"Neurology"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1093\/brain\/115.4.979","article-title":"Occurrence of a multiple sclerosis-like illness in women who have a Leber\u2019s hereditary optic neuropathy mitochondrial DNA mutation","volume":"115","author":"Harding","year":"1992","journal-title":"Brain"},{"key":"ref_134","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":"Guichet","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_135","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":"Valentino","year":"2008","journal-title":"Brain"},{"key":"ref_136","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":"ref_137","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/ana.24410","article-title":"Syndromic parkinsonism and dementia associated with OPA1 missense mutations","volume":"78","author":"Carelli","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/brain\/awr323","article-title":"The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy \u2018plus\u2019 phenotype","volume":"135","author":"Rouzier","year":"2012","journal-title":"Brain"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1001\/jamaneurol.2014.1753","article-title":"Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28","volume":"72","author":"Gorman","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/brain\/awu060","article-title":"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance","volume":"137","author":"Pfeffer","year":"2014","journal-title":"Brain"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1212\/01.wnl.0000289194.89359.a1","article-title":"Multiple sclerosis-like disorder in OPA1-related autosomal dominant optic atrophy","volume":"70","author":"Verny","year":"2008","journal-title":"Neurology"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/acn3.323","article-title":"A multiple sclerosis-like disorder in patients with OPA1 mutations","volume":"3","author":"Spyropoulos","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_143","first-page":"138","article-title":"Die komplizierte, hereditar-familiare Optikusatrophie des Kindesalters \u2013 ein bisher nicht beschriebener Symptomkomplex","volume":"47","author":"Behr","year":"1909","journal-title":"Klin Mbl. Augenheilkd."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"e321","DOI":"10.1093\/brain\/awu234","article-title":"\u2018Behr syndrome\u2019 with OPA1 compound heterozygote mutations","volume":"138","author":"Carelli","year":"2015","journal-title":"Brain"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jns.2015.07.009","article-title":"Behr syndrome with homozygous C19ORF12 mutation","volume":"357","author":"Kleffner","year":"2015","journal-title":"J. Neurol Sci."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrneurol.2014.228","article-title":"Disturbed mitochondrial dynamics and neurodegenerative disorders","volume":"11","author":"Kleffner","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nature07534","article-title":"Mitofusin 2 tethers endoplasmic reticulum to mitochondria","volume":"456","author":"Scorrano","year":"2008","journal-title":"Nature"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41580-020-0210-7","article-title":"The cell biology of mitochondrial membrane dynamics","volume":"21","author":"Giacomello","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/ng1341","article-title":"Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A","volume":"36","author":"Mersiyanova","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1212\/01.wnl.0000311275.89032.22","article-title":"Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations","volume":"70","author":"Nicholson","year":"2008","journal-title":"Neurology."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/ana.20797","article-title":"Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2","volume":"59","author":"Jordanova","year":"2006","journal-title":"Ann Neurol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.neulet.2015.04.001","article-title":"Mitochondrial dynamics and inherited peripheral nerve diseases","volume":"596","author":"Pareyson","year":"2015","journal-title":"Neurosci Lett."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1002\/humu.23639","article-title":"Insights into the genotype-phenotype correlation and molecular function of SLC25A46","volume":"39","author":"Abrams","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.15252\/emmm.201506159","article-title":"SLC 25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome","volume":"8","author":"Janer","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1002\/mds.26716","article-title":"SLC25A46 mutations underlie progressive myoclonic ataxia with optic atrophy and neuropathy","volume":"31","author":"Charlesworth","year":"2016","journal-title":"Mov Disord."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1093\/brain\/aww212","article-title":"Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia","volume":"139","author":"Wan","year":"2016","journal-title":"Brain"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"e2019665118","DOI":"10.1073\/pnas.2019665118","article-title":"Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I","volume":"118","author":"Formosa","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"109002","DOI":"10.1016\/j.celrep.2021.109002","article-title":"NDUFS3 depletion permits complex I maturation and reveals TMEM126A\/OPA7 as an assembly factor binding the ND4-module intermediate","volume":"35","author":"Astro","year":"2021","journal-title":"Cell Rep."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ajhg.2009.03.003","article-title":"TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy","volume":"84","author":"Hanein","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"e329","DOI":"10.1212\/NXG.0000000000000329","article-title":"First TMEM126A missense mutation in an Italian proband with optic atrophy and deafness","volume":"5","author":"Caporali","year":"2019","journal-title":"Neurol. Genet."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.ajhg.2015.09.012","article-title":"Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies","volume":"97","author":"Angebault","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1001\/jamaneurol.2017.2065","article-title":"Neurologic phenotypes associated with mutations in RTN4IP1 (OPA10) in children and young adults","volume":"75","author":"Charif","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"e290","DOI":"10.1097\/WNO.0000000000001124","article-title":"Combined Optic Atrophy and Rod-Cone Dystrophy Expands the RTN4IP1 (Optic Atrophy 10) Phenotype","volume":"41","author":"Rajabian","year":"2021","journal-title":"J. Neuroophthalmol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1097\/IAE.0000000000003054","article-title":"A rod-cone dystrophy is systematically associated to the RTNPIPI recessive optic atrophy","volume":"41","author":"Meunier","year":"2021","journal-title":"Retina"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Maresca, A., and Carelli, V. (2021). Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve. Biomolecules, 11.","DOI":"10.3390\/biom11040496"},{"key":"ref_166","first-page":"492","article-title":"mtDNA depletion with variable tissue expression: A novel genetic abnormality in mitochondrial diseases","volume":"48","author":"Moraes","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1167\/iovs.62.15.12","article-title":"SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance","volume":"62","author":"Jurkute","year":"2021","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1093\/brain\/awab056","article-title":"Biallelic variants in LIG3 cause a novel mito-chondrial neurogastrointestinal encephalomyopathy","volume":"144","author":"Bonora","year":"2021","journal-title":"Brain"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1093\/brain\/awab238","article-title":"Myopathic mitochondrial DNA depletion syndrome associated with biallelic variants in LIG3","volume":"144","author":"Invernizzi","year":"2021","journal-title":"Brain"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.1093\/hmg\/10.26.3093","article-title":"Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease","volume":"10","author":"Srivastava","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1038\/s41467-021-23561-7","article-title":"Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo","volume":"12","author":"Zekonyte","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/bs.mcb.2019.12.004","article-title":"Manipulation of mitochondrial genes and mtDNA heteroplasmy","volume":"155","author":"Bacman","year":"2020","journal-title":"Methods Cell Biol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"101812","DOI":"10.1016\/j.redox.2020.101812","article-title":"Idebenone: When an antioxidant is not an antioxidant","volume":"38","author":"Gueven","year":"2021","journal-title":"Redox Biol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1093\/brain\/awr170","article-title":"A randomized placebo-controlled trial of idebenone in Leber\u2019s hereditary optic neuropathy","volume":"134","author":"Klopstock","year":"2011","journal-title":"Brain"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"e188","DOI":"10.1093\/brain\/awr180","article-title":"Idebenone treatment in Leber\u2019s hereditary optic neuropathy","volume":"134","author":"Carelli","year":"2011","journal-title":"Brain"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/WNO.0000000000001023","article-title":"Real-World Clinical Experience with Idebenone in the Treatment of Leber Hereditary Optic Neuropathy","volume":"40","author":"Catarino","year":"2020","journal-title":"J. Neuroophthalmol."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Yu-Wai-Man, P., Newman, N.J., Carelli, V., La Morgia, C., Biousse, V., Bandello, F.M., Clermont, C.V., Campillo, L.C., Leruez, S., and Moster, M.L. (2021). Natural history of patients with Leber hereditary optic neuropathy-results from the REALITY study. Eye (Lond).","DOI":"10.1038\/s41433-021-01535-9"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-dose gene-replacement therapy for spinal muscular atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/joim.13046","article-title":"Strategies for fighting mitochondrial diseases","volume":"287","author":"Viscomi","year":"2020","journal-title":"J. Internal Med."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tig.2017.11.001","article-title":"Mitochondrial Genome Engineering: The Revolution May Not Be CRISPR-Ized","volume":"34","author":"Gammage","year":"2018","journal-title":"Trends Genet."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/ng851","article-title":"Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus","volume":"30","author":"Manfredi","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/ana.10354","article-title":"Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy","volume":"52","author":"Guy","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1093\/genetics\/165.2.707","article-title":"Limitations of allotopic expression of mitochondrial genes in mammalian cells","volume":"165","author":"Kenyon","year":"2003","journal-title":"Genetics"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/nar\/gkq769","article-title":"Allotopic expression of mitochondrial-encoded genes in mammals: Achieved goal, undemonstrated mechanism or impossible task?","volume":"39","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_185","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":"Newman","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.omtm.2021.09.013","article-title":"Biodistribution of intravitreal lenadogene nolparvovec gene therapy in nonhuman primates","volume":"23","author":"Calkins","year":"2021","journal-title":"Mol. Ther Methods Clin. Dev."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ophtha.2020.12.012","article-title":"Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset","volume":"128","author":"Newman","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"662838","DOI":"10.3389\/fneur.2021.662838","article-title":"Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison","volume":"12","author":"Newman","year":"2021","journal-title":"Front Neurol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"21587","DOI":"10.1038\/srep21587","article-title":"Efficacy and safety of rAAV2-ND4 treatment for Leber\u2019s hereditary optic neuropathy","volume":"6","author":"Wan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1016\/j.ophtha.2017.05.016","article-title":"Gene therapy for Leber hereditary optic neuropathy: Low- and medium-dose visual results","volume":"124","author":"Guy","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.phrs.2018.02.018","article-title":"OPA1: How much do we know to approach therapy?","volume":"131","author":"Fogazza","year":"2018","journal-title":"Pharmacol Res."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/acn3.51026","article-title":"Idebenone increases chance of stabilization\/recovery of visual acuity in OPA1-dominant optic atrophy","volume":"7","author":"Romagnoli","year":"2020","journal-title":"Ann. Clin. Transl Neurol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1093\/hmg\/ddaa244","article-title":"Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations","volume":"29","author":"Aleo","year":"2021","journal-title":"Hum Mol. Genet."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1038\/s41467-020-17821-1","article-title":"Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy","volume":"11","author":"Zaninello","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"e13579","DOI":"10.15252\/emmm.202013579","article-title":"High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts","volume":"13","author":"Cretin","year":"2021","journal-title":"EMBO. Mol. 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