2. Functions for evolutionarily conserved mitochondrial proteins

Mitochondria are dynamic and complex organelles that play a central role in all aspects of biology, including energy production, intermediary metabolism, and apoptosis. These broad cellular functions also place mitochondria as a central player in human health. Mitochondrial dysfunction is associated with a wide range of diseases, including cancer, type 2 diabetes, and most neurodegenerative disorders. As a result of these critical activities, many efforts have focused on identifying and characterizing the proteins that comprise the mitochondrial proteome, with over 1,000 proteins identified to date in mammals. Remarkably, however, one-fifth of these proteins remain largely uncharacterized. These include many proteins that are highly conserved throughout eukarya, a strong indication that they perform a fundamentally important function. Our research, in close collaboration with Jared Rutter's lab in the Biochemistry Department, is focused on functional studies of key uncharacterized mitochondrial conserved proteins (MCPs). We are conducting systematic and detailed characterization of MCP function in two simple genetic systems, yeast and Drosophila, followed by more focused studies in mammalian cells and mice. Current studies are underway characterizing the long sought after mitochondrial pyruvate transporter. Although biochemical studies in the 1970s defined this link between cytoplasmic glycolysis and mitochondrial oxidative phosphorylation, the molecular identity of the transporter has remained elusive. We have studied the function of the pyruvate transporter in yeast, Drosophila, and mammalian cells, and associated mutations in the corresponding gene with human disease. Other studies are focused on the regulation of fatty acid oxidation, a novel kinase, a regulator of Sdh, and a supercomplex assembly factor. Our goal in this project is to provide detailed insights into MCP function that can guide our understanding of how these proteins impact human health and disease.