Mitochondria are complex, essential organelles of eucaryotic organisms required for a variety of metabolic processes, including energy generation by oxidative phosphorylation and iron metabolism. Pathological effects of reduced bioenergetic capacity and altered iron metabolism are common in human populations. Understanding the essential role of molecular chaperones within mitochondria in two conserved, essential physiological processes - translocation of proteins across mitochondrial membranes and the biogenesis of Fe/S clusters - is the long term goal of this project. Since the vast majority of the hundreds of mitochondrial proteins'are synthesized on cytosolic ribosomes, efficient protein import is critical. Protein import across the mitochindrial inner membrane is driven by an import motor associated with the inner membrane translocon, having at its core the mitochondrial matrix Hsp70, Ssc1. Similarly, a conserved cellular machinery present in the mitochondrial matrix is devoted to biogenesis of Fe/S clusters, essential moieties of proteins involved in a variety of diverse cellular process. As components of this machinery, the molecular chaperones Ssq1 and Jac1, Hsp70:J-protein partners, play a critical role through interaction with their substrate protein Isu, a scaffold on which an Fe/S cluster is assembled prior to transfer to a recipient apo-protein. Primarily using S. cerevisiae as a model system and bringing to bear a combination of genetic, biochemical and cell biological approaches, a goal of the proposed experiments is to gain an understand of these mitochondrial-specific physiological processes. The results of this research will also serve as a paradigm for understanding how molecular chaperones have diverged to function in diverse physiological functions, in addition to their well-established role in general protein folding, by evolving unique, regulated interactions with other cellular components, as well as making use of biochemical properties common to all Hsp70s.
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