Journal
CELL METABOLISM
Volume 33, Issue 5, Pages 1013-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.02.001
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Funding
- 2017 AACR NextGen Grant for Transformative Cancer Research [17-20-01-LYSS]
- ACS Research Scholar grant [RSG-18-186-01]
- American Cancer Society [RSG-16-111-01-MPC]
- Jazz Pharmaceuticals VT [IST-16-10306]
- UCLA Jonsson Comprehensive Cancer Center
- Eli and Edythe Broad Center for Regenerative Medicine Ablon Scholars Program
- Most Promising Research Award from UCLA Health Innovation
- [F32CA228328]
- [P30DK034933]
- [K99CA241357]
- [1R37CA237421]
- [R01 CA215185]
- [R01 AR070245]
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Mitochondrial respiration is essential for cell proliferation by generating biosynthetic precursors like aspartate. Inhibition of electron transport chain can deplete aspartate and impair ATF4 and mTORC1 activities. Adding exogenous asparagine can restore these activities and promote cell proliferation in the context of ETC inhibition.
Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.
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