2. Academic Validation
  3. Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies

Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies

  • Cell Metab. 2015 Jun 2;21(6):823-33. doi: 10.1016/j.cmet.2015.04.012.
David Pacheu-Grau 1,  Bettina Bareth 1,  Jan Dudek 1,  Lisa Juris 1,  F-Nora Vögtle 2,  Mirjam Wissel 1,  Scot C Leary 3,  Sven Dennerlein 1,  Peter Rehling 4,  Markus Deckers 1
Affiliations

Affiliations

  • 1 Department of Cellular Biochemistry, University Medical Center Göttingen, D-37073 Göttingen, Germany.
  • 2 Institute for Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, D-79104 Freiburg, Germany.
  • 3 Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
  • 4 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.
PMID: 25959673 DOI: 10.1016/j.cmet.2015.04.012
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.

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