Cell Metabolism
Volume 21, Issue 6, 2 June 2015, Pages 823-833
Journal home page for Cell Metabolism

Article
Cooperation between COA6 and SCO2 in COX2 Maturation during Cytochrome c Oxidase Assembly Links Two Mitochondrial Cardiomyopathies

https://doi.org/10.1016/j.cmet.2015.04.012Get rights and content
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Highlights

  • COA6 is required for COX2 stability

  • COA6 interacts transiently with the catalytic domain of newly synthesized COX2

  • COA6 interacts with the copper metallochaperone SCO2

  • Mutations in SCO2 or COA6 link defects in COX2 metallation to COX deficiency in heart

Summary

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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