The Proto-oncometabolite Fumarate Binds Glutathione to Amplify ROS-Dependent Signaling
Open accessAbstract
The tricarboxylic acid cycle enzyme fumarate hydratase (FH) has been identified as a tumor suppressor in a subset of human renal cell carcinomas. Human FH-deficient cancer cells display high fumarate concentration and ROS levels along with activation of HIF-1. The underlying mechanisms by which FH loss increases ROS and HIF-1 are not fully understood. Here, we report that glutamine-dependent oxidative citric acid cycle metabolism is required to generate fumarate and increase ROS and HIF-1 levels. Accumulated fumarate directly bonds the antioxidant glutathione in vitro and in vivo to produce the metabolite succinated glutathione (GSF). GSF acts as an alternative substrate to glutathione reductase to decrease NADPH levels and enhance mitochondrial ROS and HIF-1 activation. Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS.
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High fumarate binds glutathione, augmenting ROS signaling and accumulation in vitro and in vivo.
“High concentrations of fumarate bind to glutathione, augmenting ROS signaling and accumulation, as observed in not only in vitro models but also in vivo models136,137.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [136]
As a result of the pseudohypoxic state, SDH- and FH-mutant tumors exhibit enhanced glycolytic metabolism and high ROS production.
“As a result of this “pseudohypoxic” state, SDH- and FH-mutant tumors exhibit enhanced glycolytic metabolism and high ROS production (186).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [186]
TH1 and TH17 cells rely heavily on aerobic glycolysis.
“Two pro-inflammatory T cell subsets implicated in the pathogenesis of MS, namely TH1 and TH17 cells, rely heavily on aerobic glycolysis and treatment with DMF or MMF inhibited their development in vitro, as previously reported99,101,102, 49.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [102]
Treatment with DMF or MMF inhibits development of TH1 and TH17 cells in vitro.
“Two pro-inflammatory T cell subsets implicated in the pathogenesis of MS, namely TH1 and TH17 cells, rely heavily on aerobic glycolysis and treatment with DMF or MMF inhibited their development in vitro, as previously reported99,101,102, 49.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [102]
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References 38 · Cited by 304
- Authors
- Sullivan, L. B., Martinez-Garcia, E., Nguyen, H., Mullen, A. R., Dufour, E., Sudarshan, S., Licht, J. D., Deberardinis, R. J., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- Children's Medical Center (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Chandel, Navdeep S.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 51
- Issue
- 2
- Pages
- 236-248
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3775267
- OpenAlex
- W2095860292
- Cited by
- 304
- References
- 38
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 24 · 2023: 22 · 2022: 21 · 2021: 19 · 2020: 27 · 2019: 25 · 2018: 28 · 2017: 23 · 2016: 26 · 2015: 18 · 2014: 24 · 2013: 7
- FWCI
- 8.78
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-07-25)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Northwestern University
- National Institutes of Health
- National Cancer Institute (U54CA143869, R01CA123067, R01CA157996, P30CA060553)
- National Institute of General Medical Sciences (T32 GM 08061, T32GM083831, T32GM008061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- fumarate, fumarate hydratase, glutathione, glutathione reductase, reactive oxygen species, HIF-1, renal cell carcinoma, glutamine metabolism, NADPH depletion, mitochondrial reactive oxygen species
- MeSH terms
- Carcinoma, Renal Cell, Chromatography, Liquid, Fumarate Hydratase, Fumarates, Glutathione, Glutathione Reductase, Histones, Humans, Kidney Neoplasms, NADP, Oxygen Consumption, Tumor Cells, Cultured, Immunoblotting, Signal Transduction, Reactive Oxygen Species, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, RNA, Small Interfering, NF-E2-Related Factor 2, Hypoxia-Inducible Factor 1, alpha Subunit, Histone Demethylases
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