The nuoM arg368his mutation in NADH:ubiquinone oxidoreductase from Rhodobacter capsulatus: a model for the human nd4-11778 mtDNA mutation associated with Leber's hereditary optic neuropathy.
Mutation at position 11778 in the nd4 gene of the human mitochondrial complex I is associated with Leber's hereditary optic neuropathy. Type I NADH:ubiquinone oxidoreductase of Rhodobacter capsulatus displays similar properties to complex I of the mitochondrial respiratory chain. The NUOM subunit of the bacterial enzyme is homologous to the ND4 subunit. Disruption of the nuoM gene led to a bacterial mutant exhibiting a defect in complex I activity and assembly. A nuoM-1103 point mutant reproducing the nd4-11778 mutation has been introduced in the R. capsulatus genome. This mutant showed a reduced ability to grow in a medium containing malate instead of lactate which indicated a clear impairment in oxidative phosphorylation capacity. NADH supported respiration of porous bacterial cells was significantly decreased in the nuoM-1103 mutant while no significant reduction could be observed in isolated bacterial membranes. As it has been observed in the case of the nd4-11778 mitochondrial mutation, proton-pump activity of the bacterial enzyme was not affected by the nuoM-1103 mutation. All these data which reproduce most of the biochemical features observed in patient mitochondria harboring the nd4-11778 mutation show that the R. capsulatus complex I might be used as a useful model to investigate mutations of the mitochondrial DNA which are associated with complex I deficiencies in human pathologies.
Lunardi
J
J
Laboratoire de BioEnergétique Cellulaire et Pathologique, LRA-EA 2019 UJF, DBMS, CEA, 17 rue des martyrs, 38054 Grenoble, Cedex 9, France. Joel.lunardi@cea.fr
Darrouzet
E
E
Dupuis
A
A
Issartel
J P
JP
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D002455:Cell Division / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009154:Mutation / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000235:genetics*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D010641:Phenotype; D017494:Proton Pumps / Q000502:physiology; D016354:Rhodobacter capsulatus / Q000201:enzymology* / Q000235:genetics; D016415:Sequence Alignment
D001426:Bacterial Proteins; D004272:DNA, Mitochondrial; D017494:Proton Pumps; D009247:NADH, NADPH Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D042967:Electron Transport Complex I