Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells
Cell. 2015 Jul 30;162(3):552-63. doi: 10.1016/j.cell.2015.07.017.
Lucas B Sullivan 1 , Dan Y Gui 1 , Aaron M Hosios 1 , Lauren N Bush 1 , Elizaveta Freinkman 2 , Matthew G Vander Heiden 3
1 The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
3 The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: mvh@mit.edu.
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.
Adenosine Triphosphate / metabolism
Aspartic Acid / biosynthesis*
Butyrates / metabolism
Cell Respiration*
Nucleotides / biosynthesis
Pyruvic Acid
Butyrates
alpha-ketobutyric acid
Adenosine Triphosphate
GG006413/PHS HHS/United States
P30CA1405141/CA/NCI NIH HHS/United States
Howard Hughes Medical Institute/United States