Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

H. Furkan Alkan, Katharina E. Walter, Alba Luengo, Corina T. Madreiter-Sokolowski, Sarah Stryeck, Allison N. Lau, Wael Al-Zoughbi, Caroline A. Lewis, Craig J. Thomas, Gerald Hoefler, Wolfgang F. Graier, Tobias Madl, Matthew G. Vander Heiden, Juliane G. Bogner-Strauss

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

LanguageEnglish
Pages706-720.e6
JournalCell metabolism
Volume28
Issue number5
DOIs
StatusPublished - 6 Nov 2018

Fingerprint

Glutaminase
Glutamine
Aspartic Acid
Cell Survival
Oxidation-Reduction
Homeostasis
Growth
Cell Proliferation
Carbon Cycle
Neoplasms
Allografts
Cell Death
aspartate-glutamate carrier

Keywords

  • AGC1
  • Aralar
  • aspartate-glutamate carrier
  • cancer metabolism
  • glutamine metabolism
  • SLC25A12

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cooperations

  • BioTechMed-Graz

Cite this

Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. / Alkan, H. Furkan; Walter, Katharina E.; Luengo, Alba; Madreiter-Sokolowski, Corina T.; Stryeck, Sarah; Lau, Allison N.; Al-Zoughbi, Wael; Lewis, Caroline A.; Thomas, Craig J.; Hoefler, Gerald; Graier, Wolfgang F.; Madl, Tobias; Vander Heiden, Matthew G.; Bogner-Strauss, Juliane G.

In: Cell metabolism, Vol. 28, No. 5, 06.11.2018, p. 706-720.e6.

Research output: Contribution to journalArticleResearchpeer-review

Alkan, HF, Walter, KE, Luengo, A, Madreiter-Sokolowski, CT, Stryeck, S, Lau, AN, Al-Zoughbi, W, Lewis, CA, Thomas, CJ, Hoefler, G, Graier, WF, Madl, T, Vander Heiden, MG & Bogner-Strauss, JG 2018, 'Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting', Cell metabolism, vol. 28, no. 5, pp. 706-720.e6. https://doi.org/10.1016/j.cmet.2018.07.021
Alkan HF, Walter KE, Luengo A, Madreiter-Sokolowski CT, Stryeck S, Lau AN et al. Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. Cell metabolism. 2018 Nov 6;28(5):706-720.e6. https://doi.org/10.1016/j.cmet.2018.07.021
Alkan, H. Furkan ; Walter, Katharina E. ; Luengo, Alba ; Madreiter-Sokolowski, Corina T. ; Stryeck, Sarah ; Lau, Allison N. ; Al-Zoughbi, Wael ; Lewis, Caroline A. ; Thomas, Craig J. ; Hoefler, Gerald ; Graier, Wolfgang F. ; Madl, Tobias ; Vander Heiden, Matthew G. ; Bogner-Strauss, Juliane G. / Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. In: Cell metabolism. 2018 ; Vol. 28, No. 5. pp. 706-720.e6.
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abstract = "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. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.",
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