RESEARCH

Molecular genetic regulation of cytochrome c oxidase (COX) assembly

Aerobic ATP production relies on the coordinate activity of five multimeric protein complexes localized to the inner mitochondrial membrane. One of these, COX, contains two heme and two copper moieties that are required for its catalytic activity. Their synthesis, delivery and insertion into relevant structural subunits during holoenzyme assembly is facilitated by an ever expanding number of proteins termed COX assembly factors. To date, mutations in 7 COX assembly factors have been identified that cause early onset mitochondrial diseases associated with severe, tissue-specific phenotypes with fatal clinical outcomes.

Schematic of SCO-dependent mitochondrial copper delivery to COX during holoenzyme assembly (adapted from Leary et al., 2004).

We are studying the molecular function of SCO1 and SCO2, two integral membrane proteins with crucial roles in copper delivery to COX II as it matures and is inserted into the holoenzyme. Using both genetically engineered and patient cell lines, the ultimate goal of this research is to identify and functionally characterize the relevant players that are critical to SCO-dependent metallation of COX II. This will provide for a more complete understanding of the pathways and mechanisms by which copper is delivered to COX during complex biogenesis, and may shed some light as to why two SCO proteins are essential for holoenzyme assembly in some species, while in others only a single SCO protein is required.