The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

Biomolecules. 2022 Jan 13;12(1):125. doi: 10.3390/biom12010125.

Abstract

Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the CuB and CuA sites, respectively. Biogenesis of these two copper sites of CcO occurs separately and requires a number of evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Pathogenic mutations in some of the proteins of the copper delivery pathway, such as SCO1, SCO2, and COA6, have been shown to cause fatal infantile human disorders, highlighting the biomedical significance of understanding copper delivery mechanisms to CcO. While two decades of studies have provided a clearer picture regarding the biochemical roles of SCO1 and SCO2 proteins, some discrepancy exists regarding the function of COA6, the new member of this pathway. Initial genetic and biochemical studies have linked COA6 with copper delivery to COX2 and follow-up structural and functional studies have shown that it is specifically required for the biogenesis of the CuA site by acting as a disulfide reductase of SCO and COX2 proteins. Its role as a copper metallochaperone has also been proposed. Here, we critically review the recent literature regarding the molecular function of COA6 in CuA biogenesis.

Keywords: COA6; COX2; CuA site; copper; cytochrome c oxidase; disulfide reductase; metallochaperone; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Carrier Proteins / metabolism
  • Copper* / metabolism
  • Electron Transport Complex IV* / genetics
  • Electron Transport Complex IV* / metabolism
  • Humans
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones / metabolism

Substances

  • COA6 protein, human
  • Carrier Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • SCO1 protein, human
  • Copper
  • Electron Transport Complex IV