ATP6 encodes subunit a of mitochondrial ATP synthase (Complex V), a critical component of the F0 membrane domain that generates ATP from the proton gradient across the inner mitochondrial membrane 1. ATP6 forms the proton-conducting channel together with subunit c, containing inlet and outlet half-channels that facilitate proton movement from the intermembrane space into the matrix via a Grotthuss mechanism 1. ATP synthesis couples to proton translocation through rotation of the central stalk within the catalytic F1 domain 1. Pathogenic ATP6 variants cause severe mitochondrial diseases with diverse clinical presentations. A 209-patient Leigh syndrome cohort identified MT-ATP6 as the most frequent causative gene, with specific variants (m.8993T>C and m.9176T>C) associated with ≤50% three-year survival 2. Analysis of 218 published MT-ATP6 disease cases revealed that symptomatic carriers had significantly higher heteroplasmy loads and exhibited reduced ATP synthesis rates, preserved ATP hydrolysis, and abnormally increased membrane potential—though no single biochemical feature was universally present 3. A 111-patient natural history study documented infantile-onset disease in 44% of cases with CNS involvement in 93%, muscle in 75%, and eye involvement in 46% 4. ATP6 dysfunction impairs mitochondrial respiration, causing proton accumulation in the intermembrane space, mtDNA release, and inflammasome activation 5. ATP6 variants also manifest as mitochondrial retinopathy with characteristic chorioretinal atrophy patterns 6.