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Cell Metab. 2018 Nov 6;28(5):706-720.e6. doi: 10.1016/j.cmet.2018.07.021. Epub 2018 Aug 16.

Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting.

Author information

1
Institute of Biochemistry, Graz University of Technology, Humboldtstrasse 46/III, 8010 Graz, Austria; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Institute of Biochemistry, Graz University of Technology, Humboldtstrasse 46/III, 8010 Graz, Austria.
3
The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/6, A-8010 Graz, Austria.
5
Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, A-8010 Graz, Austria.
6
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA.
7
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA; Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD 20892, USA.
8
Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, A-8010 Graz, Austria; BioTechMed-Graz, Graz, Austria.
9
Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/6, A-8010 Graz, Austria; BioTechMed-Graz, Graz, Austria.
10
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.
11
Institute of Biochemistry, Graz University of Technology, Humboldtstrasse 46/III, 8010 Graz, Austria; BioTechMed-Graz, Graz, Austria. Electronic address: juliane.bogner-strauss@tugraz.at.

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.

KEYWORDS:

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

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