As the terminal component of the mitochondrial respiratory chain,
cytochrome c oxidase plays a vital role in cellular energy transformation. Human
cytochrome c oxidase is composed of 13 subunits. The three major subunits form the catalytic core and are encoded by
mitochondrial DNA (
mtDNA). The remaining subunits are nuclear-encoded. The primary sequence is known for all human subunits and the crystal structure of bovine heart
cytochrome c oxidase has recently been reported. However, despite this wealth of structural information, the role of the nuclear encoded subunits is still poorly understood. Yeast
cytochrome c oxidase is a close model of its human counterpart and provides a means of studying the effects of mutations on the assembly, structure, stability and function of the
enzyme complex. Defects in
cytochrome c oxidase function are found in a clinically heterogeneous group of disorders. The molecular defects that underlie these diseases may arise from mutations of either mitochondrial or the nuclear genomes or both. A significant number of
cytochrome c oxidase deficiencies, often associated with other respiratory chain
enzyme defects, are attributed to mutations of
mtDNA. Mutations of
mtDNA appear, nonetheless, uncommon in early childhood. Pedigree analysis and cell fusion experiments have demonstrated a nuclear involvement in some infantile cases but a specific genomic lesion has not yet been reported. Detailed analyses of the many steps involved in the biogenesis of
cytochrome c oxidase, often pioneered in yeast, offer several starting points for further molecular characterizations of
cytochrome c oxidase deficiencies observed in clinical practice.