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.