Coordination of metal center biogenesis in human cytochrome c oxidase

Abstract

Abstract Mitochondrial cytochrome c oxidase (CcO) or respiratory chain complex IV is a heme aa 3 -copper oxygen reductase containing metal centers essential for holo-complex biogenesis and enzymatic function that are assembled by subunit-specific metallochaperones. The enzyme has two copper sites located in the catalytic core subunits. The COX1 subunit harbors the Cu B site that tightly associates with heme a 3 while the COX2 subunit contains the binuclear Cu A site. Here, we report that in human cells the CcO copper chaperones form macromolecular assemblies and cooperate with several twin CX 9 C proteins to control heme a biosynthesis and coordinate copper transfer sequentially to the Cu A and Cu B sites. These data on CcO illustrate a mechanism that regulates the biogenesis of macromolecular enzymatic assemblies with several catalytic metal redox centers and prevents the accumulation of cytotoxic reactive assembly intermediates.