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 | |
| Publication status | Published - 6 Nov 2018 |
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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 journal › Article › Research › peer-review
}
TY - JOUR
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.
KW - AGC1
KW - Aralar
KW - aspartate-glutamate carrier
KW - cancer metabolism
KW - glutamine metabolism
KW - SLC25A12
UR - http://www.scopus.com/inward/record.url?scp=85056422003&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.07.021
DO - 10.1016/j.cmet.2018.07.021
M3 - Article
VL - 28
SP - 706-720.e6
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 5
ER -