Understanding metabolic functions of mitochondria in proliferating cells

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PROJECT SUMMARY Cell metabolism is the collection of biochemical processes that support the bioenergetic, biosynthetic, and signaling demands of life. While the biochemical composition of most major human metabolic pathways have been defined, we do not yet have a strong understanding of how metabolic pathways are differentially utilized to support the diverse needs of cells across cell states. Activation of cell proliferation is one such state that comes with substantial changes to metabolic pathway activities, however many of the mechanisms by which these metabolic changes support cell proliferation, and the consequences of their disruption, remain unknown. At the heart of cell metabolism is the mitochondrion, a double membrane bound organelle that serves as a metabolic hub by providing a separate biochemical compartment from the cytosol and through the unique metabolic capabilities afforded by the electron transport chain (ETC). While most famous for its role in ATP synthesis, studies from us and others have determined that mitochondrial metabolism is essential for supporting cell proliferation independent of ATP production. These findings have upended the traditional view of mitochondria as mere “powerhouses” and underscore the need for a new, holistic understanding of how mitochondria support cell functions. Our work has identified that complex I of the ETC is critical for cell proliferation by regenerating electron acceptors, which support the synthesis of the amino acid aspartate. In addition, our preliminary data uncover that the metabolic effects of impairments to complex II of the ETC are distinct from those of complex I, and we identify a novel, redox-driven mitochondrial metabolic pathway necessary for cell proliferation upon complex II dysfunction. Nevertheless, a comprehensive understanding of the metabolic contributions of mitochondrial processes to cell proliferation remains lacking. My research program uses state-of-the-art approaches to delineate the metabolic and functional consequences of disruptions to mitochondrial processes to gain a new, systems level understanding of how the interconnected metabolic pathways in mitochondria support cell proliferation. Notably, disruptions to mitochondrial function in humans have highly diverse clinical manifestations and so mechanistic understanding of the consequences of impairments to different mitochondrial processes will support the development of novel, targeted therapeutic approaches for the many diseases associated with mitochondrial dysregulation, including inborn errors of metabolism, cancer, neurodegeneration, aging, and others.