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.