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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Transport Systems, Acidic / metabolism*
Animals
Antiporters / metabolism*
Aspartic Acid / metabolism*
Cell Line
Cell Proliferation
Cell Survival*
Citric Acid Cycle
Cytosol / metabolism*
Female
Glutamine / metabolism*
Humans
Mice, Inbred C57BL
Mitochondria / metabolism
Neoplasms / metabolism

Substances

Amino Acid Transport Systems, Acidic
Antiporters
aspartate-glutamate carrier
Glutamine
Aspartic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding