Assembly of cytochrome c oxidase: what can we learn from patients with cytochrome c oxidase deficiency?

Cytochrome c oxidase is an intricate metalloprotein that transfers electron s from cytochrome c to oxygen in the last step of the mitochondrial respira tory chain, It uses the free energy of this reaction to sustain a transmemb rane electrochemical gradient of protons. Site-directed mutagenesis studies of bacterial terminal oxidases and the recent availability of refined crys tal structures of the enzyme are rapidly expanding the understanding of the coupling mechanism between electron transfer and proton translocation. In contrast, relatively little is known about the assembly pathway of cytochro me c oxidase. Studies in yeast have indicated that assembly is dependent on numerous proteins in addition to the structural subunits and prosthetic gr oups. Human homologues of a number of these assembly factors have been iden tified and some are now known to be involved in disease. To dissect the ass embly pathway of cytochrome c oxidase, we are characterizing tissues and ce ll cultures derived from patients with genetically defined cytochrome c oxi dase deficiency, using biochemical, biophysical and immunological technique s. These studies have allowed us to identify some of the steps of the assem bly process.