Mitochondrial Genetic Diseases and Ophthalmic Manifestations: Molecular Pathophysiology, Genetics, and Clinical...

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.