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.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Arginine
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Base Sequence
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Blood Platelets / enzymology*
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Conserved Sequence
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DNA, Mitochondrial / blood
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DNA, Mitochondrial / isolation & purification
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DNA, Mitochondrial / metabolism
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Electron Transport Complex I
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Female
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Histidine
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Humans
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Kinetics
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Macromolecular Substances
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Male
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Mitochondria / enzymology*
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Molecular Sequence Data
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NADH, NADPH Oxidoreductases / blood
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NADH, NADPH Oxidoreductases / genetics*
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Optic Atrophies, Hereditary / enzymology*
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Optic Atrophies, Hereditary / genetics*
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Pedigree
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Point Mutation*
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Polymerase Chain Reaction / methods
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Rotenone / pharmacology
Substances
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DNA, Mitochondrial
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Macromolecular Substances
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Rotenone
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Histidine
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Arginine
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NADH, NADPH Oxidoreductases
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Electron Transport Complex I