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Human  SCO1  and  SCO2  code for essential metallochaperones with ill-defined functions in the biogenesis of the Cu A  site of cytochrome  c  oxidase subunit II (CO II). Here, we have used patient cell lines to investigate the specific roles of each SCO protein in this pathway. By pulse-labeling mitochondrial translation products, we demonstrate that the synthesis of CO II is reduced in  SCO2 , but not in  SCO1 , cells. Despite this biosynthetic defect, newly synthesized CO II is more stable in  SCO2  cells than in control cells. RNA i -mediated knockdown of mutant SCO2 abolishes CO II labeling in the translation assay, whereas knockdown of mutant SCO1 does not affect CO II synthesis. These results indicate that SCO2 acts upstream of SCO1, and that it is indispensable for CO II synthesis. The subsequent maturation of CO II is contingent upon the formation of a complex that includes both SCO proteins, each with a functional CxxxC copper-coordinating motif. In control cells, the cysteines in this motif in SCO1 exist as a mixed population comprised of oxidized disulphides and reduced thiols; however, the relative ratio of oxidized to reduced cysteines in SCO1 is perturbed in cells from both  SCO  backgrounds. Overexpression of wild-type SCO2, or knockdown of mutant SCO2, in  SCO2  cells alters the ratio of oxidized to reduced cysteines in SCO1, suggesting that SCO2 acts as a thiol-disulphide oxidoreductase to oxidize the copper-coordinating cysteines in SCO1 during CO II maturation. Based on these data we present a model in which each SCO protein fulfills distinct, stage-specific functions during CO II synthesis and Cu A  site maturation.

Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1