Understanding the Mechanisms of Respiratory Supercomplexes and mitochondrial Complex I

University Of California At Davis, Davis CA

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Abstract

PROJECT SUMMARY/ABSTRACT The mitochondrial oxidative phosphorylation electron transport chain (ETC) is composed of five large membrane protein complexes (CI, CII, CIII2, CIV and CV) and is responsible for the production of the majority of cellular adenosine triphosphate (ATP). Consequently, in humans the ETC is essential to bioenergetic metabolism. ETC defects are one of the most commonly diagnosed congenital metabolic defects, with CI deficiencies representing roughly a third of these diagnoses. Although ~50% of patients with CI deficiencies die within the first 2 years of life and only ~25% reach 10 years of age, there are currently no effective treatments for CI or other ETC deficiencies. This discrepancy stems in part from an incomplete understanding of the molecular mechanisms of the individual complexes and their higher-order assemblies into supercomplexes (SCs). In mammalian heart mitochondria the majority of CI is found in association with CIII2 and CIV (SC I+III2+IV, the respirasome) or in association with CIII2 (SC I+III2). Despite recent advances in our mechanistic understanding of the ETC complexes brought about by biochemical and structural work, significant questions remain regarding the function, mechanism and regulation of the complexes and SCs. To address these gaps in our understanding and to develop the basic science that will underpin potential treatment strategies of ETC defects, we will pursue three major research directions in my lab. Using detailed biochemical and enzymatic analyses together with cryo-electron microscopy structural characterizations, we will 1) elucidate the molecular mechanism and regulation of respiratory CI; 2) understand the physiological role respiratory SCs play in health and disease; and 3) characterize the biodiversity of the core metabolic respiratory pathway. To achieve this, we propose to perform systematic functional and structural comparisons of respiratory chains from mammalian mitochondria, the model invertebrate Drosophila melanogaster, the fungal model system Ustilago maydis, the planktonic protist Diplonema papillatum and the a-proteobacteria Paracoccus denitrificans. Further we will characterize respiratory complex and SC structure and function from mouse models of mitochondrial disease. Comparing respiratory metabolism from these divergent and genetically tractable organisms will allow us to test several key mechanistic hypotheses and identify conserved and divergent features of regulation. This will provide deep insights into biological energy-conserving mechanisms, which will define the scientific foundation needed for the development of therapeutic strategies against CI and further ETC deficiencies.