title: Disease-related mutations in cytochrome c oxidase studied in yeast and bacterial models.
abstract: Mitochondrial cytochrome c oxidase is a key protonmotive component of the respiratory chain. Mutations in the mitochondrially-encoded subunits of the complex have been reported in association with a range of diseases. In this work we used yeast and bacterial mutants to assess the effect of human mutations in subunit 1 (L196I) and subunit 3 (G78S, A200T, Delta F94-F98, F251L and W249Stop). While the stop mutation at the C-terminus of subunit 3 and the short deletion were highly deleterious and abolished the assembly of the mitochondrial enzyme, the four missense mutations caused little or no effect on the respiratory function. Detailed analysis of G78S, A200T and Delta F94-F98 in Rhodobacter sphaeroides confirmed and extended these observations. We show in this study that the combination of yeast and bacterial models is a useful tool to elucidate the effect of mutations in the catalytic core of cytochrome oxidase. The yeast enzyme is highly similar to the human enzyme and provides a good model to assess the deleterious effect of reported mutations. The bacterial system allows detailed biochemical analysis of the effect of the mutations on the function and assembly of the catalytic core of the enzyme.
authors.affiliation: Department of Biochemistry, University of Mississippi Medical Center, USA.
authors.forename: Melyssa
authors.initials: M
authors.lastname: Bratton
authors.forename: Denize
authors.initials: D
authors.lastname: Mills
authors.forename: C Kate
authors.initials: CK
authors.lastname: Castleden
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hosler
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D002417:Cattle; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D030342:Genetic Diseases, Inborn / Q000201:enzymology*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D009154:Mutation; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011522:Protons; D012242:Rhodobacter sphaeroides / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D005656:Fungal Proteins; D021122:Protein Subunits; D011522:Protons; D003576:Electron Transport Complex IV; D010100:Oxygen