Thursday, April 3, 2025
4/3/2025
Mitochondrial Copper Biology - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).