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      Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy.

      Febs Letters
      Amino Acid Sequence, Arginine, Base Sequence, Blood Platelets, enzymology, Conserved Sequence, DNA, Mitochondrial, blood, isolation & purification, metabolism, Electron Transport Complex I, Female, Histidine, Humans, Kinetics, Macromolecular Substances, Male, Mitochondria, Molecular Sequence Data, NADH, NADPH Oxidoreductases, genetics, Optic Atrophies, Hereditary, Pedigree, Point Mutation, Polymerase Chain Reaction, methods, Rotenone, pharmacology

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          Abstract

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

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