{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:15:56Z","timestamp":1783595756901,"version":"3.55.0"},"reference-count":62,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"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>Mitochondrial genetic disorders compromise oxidative phosphorylation (OXPHOS) and cellular energy supply, and the eye is among the first organs to feel the deficit. Photoreceptors and retinal ganglion cells (RGCs) sustain among the highest metabolic rates in the body, so ophthalmic features often dominate the clinical picture and arrive before systemic disease is recognized. More than half of all patients with confirmed mitochondrial disease develop sight-threatening complications. This review integrates mtDNA and nuclear genetics; ophthalmic and extraocular phenotypes; the bioenergetic and apoptotic mechanisms that drive vision loss; the clinical examination and investigations that delineate the problem; the differential diagnoses that must be excluded; the contribution of common mtDNA haplogroup variation to age-related retinal disease; and the diagnostic, therapeutic, and counseling approaches that turn a molecular result into useful care. Recurring themes are heteroplasmy, the threshold effect, and the selective vulnerability of RGCs and extraocular muscle across genetically distinct disorders. Treatment remains largely supportive, but idebenone, gene therapy, mitophagy modulation, and targeted antioxidants now offer mechanism-based intervention for several ophthalmic manifestations.<\/jats:p>","DOI":"10.3390\/ijms27146128","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:16:22Z","timestamp":1783592182000},"page":"6128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Genetic Diseases and Ophthalmic Manifestations: Molecular Pathophysiology, Genetics, and Clinical Management"],"prefix":"10.3390","volume":"27","author":[{"given":"Khaled K.","family":"Abu-Amero","sequence":"first","affiliation":[{"name":"Research Department, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","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_2","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_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.bbabio.2009.09.005","article-title":"Mitochondrial DNA mutations and human disease","volume":"1797","author":"Tuppen","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.oret.2020.04.027","article-title":"Subliminal Message Outer Retinal Tubulations Resembling Mitochondria in Maternally Inherited Diabetes and Deafness","volume":"4","author":"Han","year":"2020","journal-title":"Ophthalmol. Retin."},{"key":"ref_5","first-page":"789","article-title":"A neurodegenerative perspective on mitochondrial optic neuropathies","volume":"132","author":"Votruba","year":"2016","journal-title":"Ophthalmol. Retin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0197-0186(01)00129-2","article-title":"Optic nerve degeneration and mitochondrial dysfunction: Genetic and acquired optic neuropathies","volume":"40","author":"Carelli","year":"2002","journal-title":"Neurochem. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1167\/iovs.06-0295","article-title":"Mitochondrial abnormalities in patients with LHON-like optic neuropathies","volume":"47","author":"Bosley","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Abu-Amero, K.K., Almadani, B., Abualkhair, S., Hameed, S., Kondkar, A.A., Sollazzo, A., Yu, A.C., Busin, M., and Zauli, G. (2025). Mitochondrial DNA Pathogenic Variants in Ophthalmic Diseases: A Review. Genes, 16.","DOI":"10.3390\/genes16030347"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.bbamcr.2006.04.003","article-title":"Mitochondrial dynamics and disease, OPA1","volume":"1763","author":"Olichon","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1186\/s12967-025-06471-w","article-title":"OPA1 mutations in dominant optic atrophy: Domain-specific defects in mitochondrial fusion and apoptotic regulation","volume":"23","author":"Zhang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yang, T.H., Kang, E.Y., Lin, P.H., Yu, B.B., Wang, J.H., Chen, V., and Wang, N.K. (2024). Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168626"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.ajo.2005.03.017","article-title":"Hereditary optic neuropathies: From the mitochondria to the optic nerve","volume":"140","author":"Newman","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1001\/archneur.1993.00540090074013","article-title":"Ophthalmologic manifestations in MELAS syndrome","volume":"50","author":"Fang","year":"1993","journal-title":"Arch. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s11910-002-0067-5","article-title":"Chronic progressive external ophthalmoplegia","volume":"2","author":"Lee","year":"2002","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1097\/ICU.0b013e3283645ad6","article-title":"Congenital cranial dysinnervation disorders: A concept in evolution","volume":"24","author":"Bosley","year":"2013","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11910-016-0652-7","article-title":"Progressive External Ophthalmoplegia","volume":"16","author":"McClelland","year":"2016","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115","DOI":"10.4103\/0974-620X.99377","article-title":"Kearns-Sayre syndrome: An unusual ophthalmic presentation","volume":"5","author":"Ahmad","year":"2012","journal-title":"Oman J. Ophthalmol."},{"key":"ref_18","first-page":"1955","article-title":"Mitochondrial genetic background in Ghanaian patients with primary open-angle glaucoma","volume":"18","author":"Hauser","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1167\/iovs.05-1639","article-title":"Mitochondrial abnormalities in patients with primary open-angle glaucoma","volume":"47","author":"Morales","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1167\/iovs.61.12.12","article-title":"Retinal Manifestations of Mitochondrial Oxidative Phosphorylation Disorders","volume":"61","author":"Oh","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.cmet.2005.12.001","article-title":"Mitochondrial medicine: A metabolic perspective on the pathology of oxidative phosphorylation disorders","volume":"3","author":"Smeitink","year":"2006","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Visalli, F., Cappellani, F., Gagliano, G., Spinello, A., Avitabile, A., Cannizzaro, L., Capobianco, M., Gagliano, C., and Zeppieri, M. (2026). Mitochondrial Resilience in Glaucoma: Targeting NAD(+) Metabolism and Oxidative Stress in Retinal Ganglion Cell Degeneration with Nicotinamide Riboside and Berberine: Preliminary Clinical Evidence. Diseases, 14.","DOI":"10.3390\/diseases14020056"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.spen.2017.06.001","article-title":"Dominant Optic Atrophy and Leber\u2019s Hereditary Optic Neuropathy: Update on Clinical Features and Current Therapeutic Approaches","volume":"24","author":"Chun","year":"2017","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"136","DOI":"10.51329\/mehdiophthal1527","article-title":"Reactive oxygen species and oxidative stress in ocular disease: From molecular mechanisms to targeted therapies","volume":"14","author":"Abukhaled","year":"2025","journal-title":"Med. Hypothesis Discov. Innov. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mimura, T., and Noma, H. (2025). Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets. Antioxidants, 14.","DOI":"10.3390\/antiox14101251"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kenney, M.C., Hertzog, D., Chak, G., Atilano, S.R., Khatibi, N., Soe, K., Nobe, A., Yang, E., Chwa, M., and Zhu, F. (2013). Mitochondrial DNA haplogroups confer differences in risk for age-related macular degeneration: A case control study. BMC Med. Genet., 14.","DOI":"10.1186\/1471-2350-14-4"},{"key":"ref_27","first-page":"518","article-title":"The role of mitochondrial haplogroups in glaucoma: A study in an Arab population","volume":"14","author":"Morales","year":"2008","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1167\/iovs.08-2646","article-title":"Mitochondrial DNA haplogroups associated with age-related macular degeneration","volume":"50","author":"Udar","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1212\/01.WNL.0000140696.34117.95","article-title":"Mitochondrial DNA nucleotide changes in non-arteritic ischemic optic neuropathy","volume":"63","author":"Bosley","year":"2004","journal-title":"Neurology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"892","DOI":"10.2741\/4343","article-title":"Mitochondria-targeted antioxidant SkQ1 reverses glaucomatous lesions in rabbits","volume":"20","author":"Iomdina","year":"2015","journal-title":"Front. Biosci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Toma, C., Ferdeghini, D., Ola Pour, M.M., Venkatesan, S., De Cilla, S., and Grossini, E. (2026). Oxidative Stress in Diabetic Retinopathy: Pathogenic Mechanisms, Biomarkers and Clinical Implications. Antioxidants, 15.","DOI":"10.3390\/antiox15040425"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Roy, B. (2025). Pathophysiological Mechanisms of Diabetes-Induced Macrovascular and Microvascular Complications: The Role of Oxidative Stress. Med. Sci., 13.","DOI":"10.3390\/medsci13030087"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.freeradbiomed.2016.07.016","article-title":"Mitochondrial oxygen metabolism in primary human lens epithelial cells: Association with age, diabetes and glaucoma","volume":"97","author":"Kubota","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/0925-4439(94)90014-0","article-title":"Lipid peroxide and reactive oxygen species generating systems of the crystalline lens","volume":"1225","author":"Babizhayev","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2298\/SARH1210563K","article-title":"Reduced glutathione level and GSH-dependent enzyme activities in corticonuclear blocks of lenses in patients with senile cataract","volume":"140","author":"Kisic","year":"2012","journal-title":"Srp. Arh. Celok. Lek."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Njie-Mbye, Y.F., Kulkarni-Chitnis, M., Opere, C.A., Barrett, A., and Ohia, S.E. (2013). Lipid peroxidation: Pathophysiological and pharmacological implications in the eye. Front. Physiol., 4.","DOI":"10.3389\/fphys.2013.00366"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41467-020-20866-x","article-title":"Emr1 regulates the number of foci of the endoplasmic reticulum-mitochondria encounter structure complex","volume":"12","author":"Rasul","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Picca, A., Calvani, R., Coelho-Junior, H.J., Landi, F., Bernabei, R., and Marzetti, E. (2020). Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9080647"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108388","DOI":"10.1016\/j.visres.2024.108388","article-title":"Selective microRNA expression of exosomes from retinal pigment epithelial cells by oxidative stress","volume":"220","author":"Zhang","year":"2024","journal-title":"Vis. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Desjardins, P., Berthiaume, R., Couture, C., Le-Bel, G., Roy, V., Gros-Louis, F., Moulin, V.J., Proulx, S., Chemtob, S., and Germain, L. (2022). Impact of Exosomes Released by Different Corneal Cell Types on the Wound Healing Properties of Human Corneal Epithelial Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012201"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121320","DOI":"10.1016\/j.biomaterials.2021.121320","article-title":"Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration","volume":"280","author":"Tang","year":"2022","journal-title":"Biomaterials"},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"3340","DOI":"10.1167\/iovs.09-4659","article-title":"Mitochondrial DNA defects and selective extraocular muscle involvement in CPEO","volume":"51","author":"Greaves","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s40291-017-0279-7","article-title":"Genetic Counselling for Maternally Inherited Mitochondrial Disorders","volume":"21","author":"Poulton","year":"2017","journal-title":"Mol. Diagn. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zeviani, M., and Carelli, V. (2021). Mitochondrial Retinopathies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010210"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Theunissen, T.E.J., Nguyen, M., Kamps, R., Hendrickx, A.T., Sallevelt, S., Gottschalk, R.W.H., Calis, C.M., Stassen, A.P.M., de Koning, B., and Mulder-Den Hartog, E.N.M. (2018). Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00400"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3109\/07853890.2011.605389","article-title":"Diagnosis and treatment of mitochondrial myopathies","volume":"45","author":"Pfeffer","year":"2013","journal-title":"Ann. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1212\/WNL.0b013e318238863a","article-title":"POLG-related disorders: Defects of the nuclear and mitochondrial genome interaction","volume":"77","author":"Milone","year":"2011","journal-title":"Neurology"},{"key":"ref_49","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_50","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_51","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13024-026-00950-4","article-title":"Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration","volume":"21","author":"Maddineni","year":"2026","journal-title":"Mol. Neurodegener."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1212\/01.WNL.0000151976.60624.01","article-title":"L-arginine improves the symptoms of strokelike episodes in MELAS","volume":"64","author":"Koga","year":"2005","journal-title":"Neurology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/ajmg.1380","article-title":"Mitochondrial disorders: Genetics, counseling, prenatal diagnosis and reproductive options","volume":"106","author":"Thorburn","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kaminer Abargel, M., Macarov, M., Hendler, K., and Yahalom, C. (2025). The importance of genetic counselling and testing in inherited eye diseases: A population-based retrospective study. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0318492"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kar, B., Castillo, S.R., Sabharwal, A., Clark, K.J., and Ekker, S.C. (2023). Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065798"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/s41467-022-28358-w","article-title":"In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue","volume":"13","author":"Nash","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"eadr0792","DOI":"10.1126\/scitranslmed.adr0792","article-title":"Correcting a pathogenic mitochondrial DNA mutation by base editing in mice","volume":"17","author":"Bacman","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.mito.2021.12.006","article-title":"Standpoints in mitochondrial dysfunction: Underlying mechanisms in search of therapeutic strategies","volume":"63","author":"Videla","year":"2022","journal-title":"Mitochondrion"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wicinski, M., Fajkiel-Madajczyk, A., Kurant, Z., Rzepinski, L., and Slupski, M. (2026). Review of Therapeutic Potential of Coenzyme Q10 in Ophthalmology: Focus on Age-Related Macular Degeneration, Glaucoma, and Retinitis Pigmentosa. Antioxidants, 15.","DOI":"10.3390\/antiox15040506"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"110505","DOI":"10.1016\/j.exer.2025.110505","article-title":"Human induced pluripotent stem cell-derived extracellular vesicles promote neuroprotection effects in rat optic nerve crush model","volume":"258","author":"Lu","year":"2025","journal-title":"Exp. Eye Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Park, M., Kim, H.M., Shin, H.A., Lee, S.H., Hwang, D.Y., and Lew, H. (2021). Human Pluripotent Stem Cell-Derived Neural Progenitor Cells Promote Retinal Ganglion Cell Survival and Axon Recovery in an Optic Nerve Compression Animal Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212529"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s13287-023-03500-7","article-title":"Intravitreal allogeneic mesenchymal stem cells: A non-randomized phase II clinical trial for acute non-arteritic optic neuropathy","volume":"14","author":"Pastor","year":"2023","journal-title":"Stem Cell Res. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6128\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:18:03Z","timestamp":1783592283000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":62,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146128"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146128","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}