- Molecular genetic regulation of cellular copper homeostasis
Ph.D., 2001, Queen's University, Department of Biology
B.Sc.., 1995, University of Guelph, Department of Zoology
Mitochondria are cellular organelles that have long been recognized for their essential role in producing ATP, the chemical form of energy required to fuel a diverse range of biochemical reactions within the cell. In the last decade or so, however, additional roles for mitochondria in a myriad of other homeostatic pathways within the cell have been identified (e.g. apoptosis, non-shivering thermogenesis, iron- sulphur cluster biogenesis, cellular copper homeostasis). We are interested in identifying and characterizing the molecular genetic mechanisms that allow mitochondria to make so many varied, and fundamental, contributions to cell biology.
Molecular genetic regulation of cellular copper homeostasis
Copper is an essential micronutrient that is required as a cofactor for the enzymatic activity of several cellular proteins; however, it is also extremely cytotoxic when free in the cell. Highly conserved mechanisms therefore have evolved for its safe acquisition, distribution and storage. While individual pathways responsible for particular facets of intracellular copper handling have been fairly well studied in isolation, very little is known about how their collective activity is regulated at the cellular level, and how copper is prioritized when its abundance becomes rate-limiting.
Schematic of cellular copper handling, with special emphasis on the SCO-dependent, mitochondrial signaling pathway that impinges upon as of yet unknown cellular targets to modulate the rate of copper efflux from the cell.
A prominent role for mitochondria in regulating cellular copper homeostasis is now appreciated, and provides a unique opportunity to investigate the mechanistic basis that allows for connectivity between discrete cellular copper trafficking pathways. Using a number of complementary experimental paradigms, our ultimate goal is to genetically and physically map the hierarchical network that regulates cellular copper levels, and ensures copper is appropriately distributed throughout the cell. Such studies are crucial to our mechanistic understanding of the tissue-specific diseases that result from a failure to properly regulate total cellular copper levels or deliver copper to relevant protein targets (e.g. Menkes disease).
- Bourens, M., A. Boulet, S.C. Leary and A. Barrientos. 2014. Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase. Hum. Mol. Genet. 23: 2901-2913.
- Vest, K.E., S.C. Leary, D.R. Winge and P.A. Cobine. 2013. Pic2 mediates import of copper into the mitochondrial matrix in Saccharomyces cerevisiae. J. Biol. Chem. 288: 23884-23892.
- Leary, S.C.,* H. Antonicka,* F. Sasarman, W. Weraarpachai, P.A. Cobine, M. Pan, G.K. Brown, R. Brown, J. Majewski, J. Swartzentruber, S. Rahman, and E.A. Shoubridge. 2013. Novel mutations in SCO1 as a cause of fatal infantile encephalopathy and lactic acidosis. Hum. Mutat. 34: 1366-1370.
- Leary, S.C.,† P.A. Cobine, T. Nishimura, R.M. Verdijk, R. de Krijger, R. de Coo, M.A. Tarnopolsky, D.R. Winge and E.A. Shoubridge. 2013. COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux. Mol. Biol. Cell. 24: 683-691.
- Dodani, S.C., Leary, S.C., Cobine, P.A., Winge, D.R. and Chang, C.J. 2011. A targetable fluorescent sensor reveals that copper-deficient SCO1 and SCO2 patient cells prioritize mitochondrial copper homeostasis. J. Am. Chem. Soc. 133: 8606-8616.