Mitochondrial Biology&Cellular Metal Ion Homeostasis

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 handing
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 (Leary et al., 2007, Leary et al., 2013, Baker et al., 2017), and provides a unique opportunity to investigate the mechanistic basis that allows for connectivity between discrete cellular copper trafficking pathways. Using a number of transgenic animal models (e.g. Hlynialuk et al., 2015, Baker et al., 2017) and cell culture systems, our ultimate goal is to genetically and physically map how the mitochondrion fits into the hierarchical network that ensures copper is appropriately distributed throughout the cell. Such studies are crucial to our understanding of 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).