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

doi:10.1016/j.cmet.2018.07.021

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

^*Corresponding author for this work

Institute of Biochemistry (6480)

Research output: Contribution to journal › Article › peer-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.

Original language	English
Pages (from-to)	706-720.e6
Journal	Cell Metabolism
Volume	28
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2018.07.021
Publication status	Published - 6 Nov 2018

Keywords

AGC1
Aralar
aspartate-glutamate carrier
cancer metabolism
glutamine metabolism
SLC25A12

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Cooperations

BioTechMed-Graz

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2018.07.021

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Alkan, H. F., Walter, K. E., Luengo, A., Madreiter-Sokolowski, C. T., Stryeck, S., Lau, A. N., Al-Zoughbi, W., Lewis, C. A., Thomas, C. J., Hoefler, G., Graier, W. F., Madl, T., Vander Heiden, M. G., & Bogner-Strauss, J. G. (2018). Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. Cell Metabolism, 28(5), 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, 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

@article{ed24d8250a384fb69aec3ba268c30ff5,

title = "Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting",

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.",

keywords = "AGC1, Aralar, aspartate-glutamate carrier, cancer metabolism, glutamine metabolism, SLC25A12",

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

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doi = "10.1016/j.cmet.2018.07.021",

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T1 - Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

AU - Alkan, H. Furkan

AU - Walter, Katharina E.

AU - Luengo, Alba

AU - Madreiter-Sokolowski, Corina T.

AU - Stryeck, Sarah

AU - Lau, Allison N.

AU - Al-Zoughbi, Wael

AU - Lewis, Caroline A.

AU - Thomas, Craig J.

AU - Hoefler, Gerald

AU - Graier, Wolfgang F.

AU - Madl, Tobias

AU - Vander Heiden, Matthew G.

AU - Bogner-Strauss, Juliane G.

PY - 2018/11/6

Y1 - 2018/11/6

N2 - 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.

AB - 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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Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

Abstract

Keywords

ASJC Scopus subject areas

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UN SDGs

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