Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells

By Lucas B. Sullivan, D. Y. Gui, Aaron M. Hosios, Lauren N. Bush, Elizaveta Freinkman, M. V. Vander Heiden. Cell, 2015

1,066 citations recorded by the source corpus.

Summary Mitochondrial respiration is important for cell proliferation, however the specific metabolic requirements fulfilled by respiration to support proliferation have not been defined. Here we show that a major role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis. This finding is consistent with the observation that cells lacking a functional respiratory chain are auxotrophic for pyruvate, which serves as an exogenous electron acceptor. Further, the pyruvate requirement can be fulfilled with an alternative electron acceptor, alpha-ketobutyrate, which provides cells neither carbon nor ATP. Alpha-ketobutyrate restores proliferation when respiration is inhibited, suggesting that an alternative electron acceptor can substitute for respiration to support proliferation. We find that electron acceptors are limiting for producing aspartate, and supplying aspartate enables proliferation of respiration deficient cells in the absence of exogenous electron acceptors. Together, these data argue a major function of respiration in proliferating cells is to support aspartate synthesis.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/149774b51e554390ea6823f2605b9cf7bc6458a3

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Citations in the corpus

Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer (2016, background): “This suggests that oxidative glucose metabolism may provide benefits to tumor cells such as the production of aspartate (Sullivan et al., 2015), regardless of tumor size.”
Mitochondrial metabolism and cancer (2017, background): “Although in vitro, under optimal growth conditions (which differ significantly from those encountered in the tumor microenvironment in vivo), cancer cells can obtain sufficient ATP from glycolysis, mitochondria are required for proliferation unless supraphysiological amounts of uridine and pyruvate ”
Understanding the intersections between metabolism and cancer biology (2017, positive): “Regenerating NAD+ via orthogonal pathways can also increase cell proliferation when respiration is impaired (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016), and disposal of excess electrons can limit proliferation in prokaryotic systems (Dietrich et al.”
Mitochondria and Cancer (2016, background): “Ketobutyrate, which only fulfills the electron acceptor role, can also support aspartate synthesis and cell growth (Sullivan et al., 2015).”
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “Adaptation of cancer cells to glucose deprivation occurs through the ability to exploit alternative fuel sources, including acetate, glutamine, and aspartate (Jaworski et al., 2016; Sullivan et al., 2015).”
One-Carbon Metabolism in Health and Disease. (2017, background): “…cells, which are depleted for mitochondrial DNA, no alterations in folate metabolism were observed (Patel et al., 2003); however, these cells require exogenous pyruvate to grow, which functions in part to restore the NAD+/NADH ratio (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016).”
Targeting Metabolism for Cancer Therapy (2017, background): “Proliferating cells often require a high NAD+/NADH ratio to support anabolic reactions, and in some contexts the NAD+/NADH ratio directly correlates with proliferation rate (Gui et al., 2016).”