Cell Metabolism
Volume 28, Issue 5, 6 November 2018, Pages 706-720.e6
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Article
Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

https://doi.org/10.1016/j.cmet.2018.07.021Get rights and content
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Highlights

  • Cells lacking the mitochondrial aspartate exporter (AGC1) require glutamine metabolism

  • Cytosolic aspartate is required to sustain survival when glutamine is limiting

  • Glutamine anaplerosis supports aspartate production

  • AGC1 loss sensitizes tumors to glutaminase inhibition in vivo

Summary

Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

Keywords

cancer metabolism
glutamine metabolism
AGC1
Aralar
SLC25A12
aspartate-glutamate carrier

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