Grant: Operating Grant - PA: Regional Partnership Program - Saskatchewan

Mitochondria are small cellular compartments that produce the chemical form of energy (ATP) that supports normal cell function. ATP is produced by the concerted efforts of a number of enzyme complexes. Deficiencies in one of these complexes, cytochrome c oxidase (COX), are associated with a broad spectrum of clinical presentations from isolated myopathies to multisystem disease. SCO1 and SCO2 are two closely related genes involved in delivering copper, an essential co-factor, to COX during its assembly. I recently discovered that SCO proteins also fulfill additional, and unexpected, roles in regulating how the cell handles copper, to minimize the potential toxicity of this essential metal as it is trafficked throughout the cell. Much remains to be learned, however, about how a SCO-dependent mitochondrial signal is generated and subsequently transduced to extra-mitochondrial compartments, to effect changes in cellular copper homeostasis. The overall goal of this research proposal therefore is to identify and characterize the mitochondrial and non-mitochondrial components of this signaling pathway, so as to understand how this pathway ultimately impinges upon the global regulation of cellular copper homeostasis. This may lead to the development of novel therapies with which to treat human diseases that result from an isolated COX deficiency or cellular copper handling defects.