Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells
Open accessAbstract
The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
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α-KG supports self-renewal of naive murine embryonic stem cells by promoting histone and DNA demethylation.
“In addition to its role in cancer cells, α-KG supports the self-renewal of naive murine embryonic stem cells (mESCs) by promoting histone and DNA demethylation104.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [104]
The effect of αKG on cell fate is likely context specific, as interventions that increase αKG levels in mouse ESCs favor self-renewal over differentiation.
“However, the effect of αKG on cell fate is likely context specific as interventions that increase αKG levels in mouse ESCs favor self-renewal over differentiation (165, 166).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [165]
Naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin.
“Moreover, naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin (165, 211, 212, 213, 214).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [165]
The glutamine-independent phenotype exhibited by naïve mouse ESCs is coupled with a reduction in the contribution of glutamine-derived carbons to TCA cycle intermediates.
“The glutamine-independent phenotype exhibited by naïve mouse ESCs is coupled with a reduction in the contribution of glutamine-derived carbons to TCA cycle intermediates (165).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [165]
Naïve mouse ESCs can grow in the absence of exogenous glutamine.
“While most cultured cell lines require glutamine supplementation to support cell survival and proliferation, naïve mouse ESCs can grow in the absence of exogenous glutamine.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [165]
Some cell types, such as embryonic stem cells and luminal breast cancer cells, can proliferate without glutamine in culture medium, indicating de novo glutamine production in some contexts.
“Interestingly, some cell types, such as embryonic stem cells and luminal breast cancer cells, are capable of proliferating in the absence of glutamine in the culture medium, indicating that in some cellular contexts, glutamine can be produced de novo (Carey et al., 2015; Kung et al., 2011).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Carey et al., 2015
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- Authors
- Carey, B. W., Finley, L. W. S., Cross, J. R., Allis, C. D., & Thompson, C. B.
- Affiliations
- Rockefeller University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Allis, C. David
- Thompson, Craig B.
- Venue
- Nature
- Published
- 2014-12-10
- Volume
- 518
- Issue
- 7539
- Pages
- 413-416
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4336218
- OpenAlex
- W2087814592
- Cited by
- 1,007
- References
- 31
- Citations by year
- 2026: 82 · 2025: 92 · 2024: 74 · 2023: 84 · 2022: 101 · 2021: 92 · 2020: 110 · 2019: 95 · 2018: 63 · 2017: 85 · 2016: 90 · 2015: 39
- FWCI
- 29.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA105463, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- alpha-ketoglutarate, succinic acid, glutamine metabolism, glucose metabolism, naive pluripotency, mouse embryonic stem cells, histone demethylation, DNA demethylation, H3K27me3, TET enzymes, chromatin modification, stem cell self-renewal, cell differentiation, epigenetic regulation, cellular metabolism
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Cell Membrane Permeability, Chromatin, Glucose, Histones, Ketoglutaric Acids, Methylation, Transcription, Genetic, Glutamic Acid, DNA Methylation, Succinic Acid, Pluripotent Stem Cells, Intracellular Space, Epigenesis, Genetic, Cell Proliferation, Mice, Embryonic Stem Cells
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