Serine Catabolism Regulates Mitochondrial Redox Control during Hypoxia
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Abstract
The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+, resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP+ ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival. Significance: In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth. Cancer Discov; 4(12); 1406–17. ©2014 AACR. See related commentary by Martínez-Reyes and Chandel, p. 1371 This article is highlighted in the In This Issue feature, p. 1355
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SHMT2 is unlikely to directly demethylate trigonelline because it is not a N-methyltransferase and is known to cross-talk with NAD+ metabolism indirectly.
“SHMT2 is unlikely to directly demethylate trigonelline because it is not a N-methyltransferase and is known to cross-talk with NAD+ metabolism indirectly37,38.”
From Trigonelline Is an NAD+ Precursor That Improves Muscle Function during Ageing and Is Reduced in Human Sarcopenia (2024) · cites this paper as [37]
Loss of SHMT2 in hypoxic cells increases reactive oxygen species levels, resulting in cell death.
“Loss of SHMT2 in hypoxic cells increases reactive oxygen species (ROS) levels, resulting in cell death.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [61]
SHMT2 plays a role in redox balance.
“SHMT2 also plays a role in redox balance.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [126]
Hypoxia induces SHMT2 expression, and SHMT2 is necessary for redox homeostasis and cell survival under hypoxic conditions.
“Hypoxia induces SHMT2 expression and was found to be necessary for redox homeostasis and cell survival under hypoxic conditions.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [126]
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- Authors
- Ye, J., Fan, J., Venneti, S., Wan, Y.-W., Pawel, B. R., Zhang, J., Finley, L. W. S., Lu, C., Lindsten, T., Cross, J. R., Qing, G., Liu, Z., Simon, M. C., Rabinowitz, J. D., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Princeton University (US)
- Baylor College of Medicine (US)
- Children's Hospital of Philadelphia (US)
- 1Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
- Huazhong University of Science and Technology (CN)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-12-01
- Volume
- 4
- Issue
- 12
- Pages
- 1406-1417
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4258153
- OpenAlex
- W2163404652
- Cited by
- 452
- References
- 50
- Citations by year
- 2026: 31 · 2025: 29 · 2024: 40 · 2023: 38 · 2022: 46 · 2021: 58 · 2020: 67 · 2019: 36 · 2018: 21 · 2017: 27 · 2016: 34 · 2015: 19 · 2014: 5
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Cancer Institute (K08CA181475, P01CA104838, K99CA184239, R01CA105463, P30CA008748, R01CA163591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- serine catabolism, SHMT2, hypoxia, mitochondrial redox balance, NADPH/NADP+ ratio, reactive oxygen species, c-Myc, tumor growth, neuroblastoma, hypoxia-inducible factor-1α, hypoxia-induced cell death, cancer metabolism
- MeSH terms
- Animals, Hypoxia, Base Sequence, Cell Survival, Disease Models, Animal, Gene Amplification, Homeostasis, Humans, Mitochondria, Models, Biological, Molecular Sequence Data, Neoplasms, Oxidation-Reduction, Promoter Regions, Genetic, Serine, Glycine Hydroxymethyltransferase, Gene Expression, Genes, myc, Reactive Oxygen Species, Cell Line, Tumor, Tumor Burden, Phosphoglycerate Dehydrogenase, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Gene Knockdown Techniques, Heterografts
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