title: Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy.
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.
authors.affiliation: Department of Biology, Institute of Clinical Neurology, University of Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Degli Esposti
authors.forename: V
authors.initials: V
authors.lastname: Carelli
authors.forename: A
authors.initials: A
authors.lastname: Ghelli
authors.forename: M
authors.initials: M
authors.lastname: Ratta
authors.forename: M
authors.initials: M
authors.lastname: Crimi
authors.forename: S
authors.initials: S
authors.lastname: Sangiorgi
authors.forename: P
authors.initials: P
authors.lastname: Montagna
authors.forename: G
authors.initials: G
authors.lastname: Lenaz
authors.forename: E
authors.initials: E
authors.lastname: Lugaresi
authors.forename: P
authors.initials: P
authors.lastname: Cortelli
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine; D001483:Base Sequence; D001792:Blood Platelets / Q000201:enzymology*; D017124:Conserved Sequence; D004272:DNA, Mitochondrial / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism; D042967:Electron Transport Complex I; D005260:Female; D006639:Histidine; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D009247:NADH, NADPH Oxidoreductases / Q000097:blood / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D012402:Rotenone / Q000494:pharmacology
chemical_list: D004272:DNA, Mitochondrial; D046911:Macromolecular Substances; D012402:Rotenone; D006639:Histidine; D001120:Arginine; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I