Abstract
Deficiencies in the mitochondrial cytochrome c oxidase (COX) or complex IV, the last enzyme of the mitochondrial respiratory chain, are a frequent cause of mitochondrial diseases in human. Eukaryotic COX is a multimeric copper-heme a, a3-type oxidase, formed by three catalytic core subunits encoded in the mitochondrial genome and ten nuclear-encoded subunits that act as a protective shield of the core. The biogenesis of the catalytic core subunits, the incorporation of their metal prosthetic groups, and their assembly with imported subunits synthesized in the cytoplasm, involves a growing number of nuclear-encoded ancillary factors. Mutations in the structural subunits and in the assembly factors have been recognized over the last 15 years as important causes of human diseases. In this chapter, we review the current knowledge on human COX biogenesis and discuss the molecular basis of human COX deficiencies due to mutations in proteins involved in the COX assembly process.