Coordination of metal center biogenesis in human cytochrome c oxidase

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.