PROJECT SUMMARY
Copper is an essential micronutrient required for the growth and development of aerobic organisms. Copper
serves as a catalytic cofactor for many enzymes involved in various cellular pathways, the most important of
which is cytochrome c oxidase required for mitochondrial energy generation. Not surprisingly, mutations that
cause systemic or subcellular copper deficiency give rise to various fatal infantile disorders, including Menkes
disease and a subset of mitochondrial disorders. Despite decades of work, there are currently no approved
treatments for these lethal disorders, which in large part reflects a limited understanding of the mechanisms by
which copper is trafficked to mitochondria and the role it plays in mitochondrial metabolism. Filling this knowledge
gap will require a multidisciplinary approach that leverages the strengths of different model organisms to
understand the mechanisms by which copper is transported, stored, and distributed within cells. Over the last
decade, we have taken a multidisciplinary approach to discover new players in copper transport and delivery to
mitochondrial cytochrome c oxidase. Through these efforts, we have identified a promising copper-transporting
drug, elesclomol, that circumvents disease-causing mutations in the mitochondrial copper acquisition by
promoting copper delivery to cytochrome c oxidase and restoring aerobic respiration. Building on this success,
we will now focus on identifying critical regulators of mitochondrial copper by leveraging our copper-deficient
yeast, zebrafish, and mouse models to decipher the fundamental roles of copper in mitochondrial metabolism.
The overarching goals of our research program are to 1) determine the molecular mechanisms of mitochondrial
copper acquisition and delivery to cytochrome c oxidase; 2) identify novel roles of copper within the mitochondrial
matrix; and 3) develop small molecule adjuvants to enhance the efficacy and safety of elesclomol. To achieve
these goals, we will employ genomic, proteomic, and small molecule screens in copper-deficient yeast models
to identify endogenous copper-transporting molecules, new copper-dependent mitochondrial metabolic
pathways, and small molecules that improve the therapeutic properties of elesclomol. We will translate these
discoveries to mammalian model systems to significantly advance our understanding of mitochondrial copper
biology.