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.
Highlights
Cytochrome c oxidase (CcO) is the terminal enzyme of the mitochondrial respiratory chain (MRC) that catalyzes the reduction of molecular oxygen to water using electrons from cytochrome c [1]
Elucidating the biochemical function of these cytochrome c oxidase (CcO) assembly bly factors has remained a major bottleneck in our understanding of the biogenesis of CcO, factors has remained a major bottleneck in our understanding of the biogenesis of CcO, with the role of COA6 in CuA site formation being a case in point
A recent review article with the role of COA6 in CuA site formation being a case in point
Summary
Cytochrome c oxidase (CcO) is the terminal enzyme of the mitochondrial respiratory chain (MRC) that catalyzes the reduction of molecular oxygen to water using electrons from cytochrome c [1]. Metallochaperones, SCO2, COA6, and COX19 have been shown to be a part of the copper delivery pathway in the IMS [21,23,24,28,29]. COX17 receives copper in was the IMS identified as a putative assembly factor based on an iterative orthology prediction via an unknown mechanism and transfers it to COX11 and SCO1, which metallates [31]. Based on its sub-mitochondrial localization, human genetics, and protein sequence, we predicted the role of Coa in the copper delivery pathway to CcO [21]. Copper supplementation in the yeast growth media rescued respiratory growth and CcO assembly of coa6∆ cells, providing the first link between Coa and the mitochondrial copper delivery pathway to CcO [21]. Co-immunoprecipitation of Coa identified specific interaction of Coa with proteins involved in the CuA site biogenesis, including Sco, Sco, and Cox2 [23]. These studies together, unequivocally place COA6 in the final steps of CuA site biogenesis
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