ND4 encodes a core subunit of mitochondrial respiratory complex I (NADH dehydrogenase), which catalyzes electron transfer from NADH through the respiratory chain using ubiquinone as an electron acceptor 1. This mitochondrially encoded protein is essential for the catalytic activity and assembly of complex I, playing a crucial role in oxidative phosphorylation within retinal ganglion cells 2. The most common disease-causing mutation is m.11778G>A in the MT-ND4 gene, which leads to Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disease causing severe visual impairment primarily in young adult males 3. This mutation impairs complex I function, leading to mitochondrial dysfunction, oxidative stress, and ultimately irreversible retinal ganglion cell death 4. Patient-derived cells show defective neurite outgrowth, decreased basal respiration, and reduced antioxidant enzyme expression 4. LHON exhibits incomplete penetrance, with some carriers remaining asymptomatic despite harboring the mutation 2. Recent gene therapy approaches using rAAV2/2-ND4 (lenadogene nolparvovec) have shown promising results, with sustained bilateral visual improvement observed up to 5 years after unilateral intravitreal injection 5. Meta-analyses demonstrate superior visual recovery rates with gene therapy compared to idebenone treatment or natural history 6.