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Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting
H Furkan Alkan1, Katharina E Walter2, Alba Luengo3
1Institute 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.
Cell Metabolism
|August 21, 2018
Summary
Mitochondrial aspartate export via aspartate-glutamate carrier 1 (AGC1) is crucial for cell proliferation and survival. Inhibiting AGC1 can synergize with glutaminase inhibitors to limit tumor growth, especially in low-glutamine conditions.
Area of Science:
- Cell Biology
- Metabolic Pathways
- Cancer Research
Background:
- Mitochondrial function is vital for cellular processes, including aspartate biosynthesis necessary for proliferating cells.
- Aspartate availability influences cell survival, redox balance, and metabolic pathways.
- The aspartate-glutamate carrier 1 (AGC1) facilitates metabolite exchange between mitochondria and cytosol.
Purpose of the Study:
- To investigate the role of mitochondrial aspartate export mediated by AGC1 in cell proliferation and redox homeostasis.
- To determine the impact of AGC1 function on cell survival under conditions of limited nutrient supply (glutamine withdrawal) or metabolic inhibition.
- To evaluate the therapeutic potential of targeting AGC1, alone or in combination with glutaminase inhibitors, in cancer models.
Main Methods:
- Utilized cell culture models to study the effects of AGC1 manipulation on cell proliferation and viability.
- Employed glutamine withdrawal and glutaminase inhibition (using CB-839) to create nutrient-limited or metabolically stressed conditions.
- Assessed tumor growth in allograft models to evaluate the in vivo efficacy of AGC1 inhibition and combination therapies.
Main Results:
- Mitochondrial aspartate export via AGC1 is essential for supporting cell proliferation and maintaining cellular redox homeostasis.
- Reduced cytosolic aspartate levels, caused by impaired AGC1 function or glutamine deprivation/glutaminase inhibition, lead to cell death.
- Loss of AGC1 function significantly reduces allograft tumor growth, with further compromise observed upon treatment with the glutaminase inhibitor CB-839.
Conclusions:
- Mitochondrial aspartate export is a critical survival mechanism for cells, particularly in low-glutamine environments.
- AGC1 plays a key role in sustaining cell viability by ensuring adequate cytosolic aspartate supply.
- Targeting AGC1 presents a potential therapeutic strategy that can synergize with glutaminase inhibitors to inhibit tumor growth.
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