title: Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.
abstract: Three mitochondria-encoded subunits form the catalytic core of cytochrome c oxidase, the terminal enzyme of the respiratory chain. COX1 and COX2 contain heme and copper redox centers, which are integrated during assembly of the enzyme. Defects in this process lead to an enzyme deficiency and manifest as mitochondrial disorders in humans. Here we demonstrate that COA6 is specifically required for COX2 biogenesis. Absence of COA6 leads to fast turnover of newly synthesized COX2 and a concomitant reduction in cytochrome c oxidase levels. COA6 interacts transiently with the copper-containing catalytic domain of newly synthesized COX2. Interestingly, similar to the copper metallochaperone SCO2, loss of COA6 causes cardiomyopathy in humans. We show that COA6 and SCO2 interact and that corresponding pathogenic mutations in each protein affect complex formation. Our analyses define COA6 as a constituent of the mitochondrial copper relay system, linking defects in COX2 metallation to cardiac cytochrome c oxidase deficiency.
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Pacheu-Grau
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bareth
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Dudek
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Juris
authors.affiliation: Institute for Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: F-Nora
authors.initials: FN
authors.lastname: Vögtle
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Wissel
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Scot C
authors.initials: SC
authors.lastname: Leary
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Dennerlein
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany; Max-Planck Institute for Biophysical Chemistry, D-37077, Göttingen, Germany. Electronic address: Peter.Rehling@medizin.uni-goettingen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Rehling
authors.affiliation: Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Deckers
mesh_terms: D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D012441:Saccharomyces cerevisiae
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C400285:SCO2 protein, human; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV