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 novel role for mitochondria in regulating copper efflux from the cell was recently discovered (Leary et al., 2007), 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, the ultimate goal of this research 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.