FUNCTIONAL ALTERATIONS OF THE MITOCHONDRIALLY ENCODED ND4 SUBUNIT ASSOCIATED WITH LEBERS HEREDITARY OPTIC NEUROPATHY

Leber's hereditary optic neuropathy (LHON) is a maternally inherited d isease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide p osition 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH:ubiquinone reducta se (respiratory complex I). We report that this amino acid substitutio n alters the affinity of complex I for the ubiquinone substrate and in duces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in th e energy conserving function of NADH:ubiquinone reductase and thus exp lain the pathological effect of the ND4/11,778 mutation.