Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells

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 sy...

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Bibliographic Details
Published in:Cell 2015-07, Vol.162 (3), p.552-563
Main Authors: Sullivan, Lucas B., Gui, Dan Y., Hosios, Aaron M., Bush, Lauren N., Freinkman, Elizaveta, Vander Heiden, Matthew G.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Aspartic Acid - biosynthesis
Butyrates - metabolism
Cell Line, Tumor
Cell Proliferation
Cell Respiration
Electrons
Humans
Mitochondria - metabolism
Nucleotides - biosynthesis
Pyruvic Acid
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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. [Display omitted] •Electron acceptor deficiency limits respiration-deficient cell proliferation•Electron acceptor α-ketobutyrate supports respiration-deficient cell proliferation•Aspartate supports proliferation in the absence of electron acceptors•A primary role of respiration in proliferating cells is to produce aspartate A primary role of respiration in proliferating cells is to support aspartate synthesis.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.07.017