Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells

By Bryce W. Carey, Lydia W. S. Finley, Justin R. Cross, C. D. Allis, Craig B. Thompson. Nature, 2014

874 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2c15b2819182b8b46846225a02a592195080c00a

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Citations in the corpus

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination (2016, background): “Expanding on the crucial role of mTORC1 in nutrient sensing, several amino acid pathways have been reported to be essential for the maintenance of PSC properties (Wang et al., 2009; Carroll et al., 2016; Shiraki et al., 2014; Carey et al., 2015).”
The Mitochondrial Basis of Aging (2016, background): “For example, one recent study demonstrated that, in mouse embryonic stem (ES) cells, the intracellular ratio of a-ketoglutarate (aKG) to succinate was important in maintaining pluripotency (Carey et al., 2015).”
The SH-SY5Y cell line in Parkinson’s disease research: a systematic review (2017, positive): “histone-lysine demethylases and DNA demethylases [14].”
Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “In contrast, enhanced activity of α-ketoglutarate-dependent DNA demethylases and histone demethylases causes histone and DNA demethylation that enhances pluripotency in embryonic stem cells (119).”
Epigenetic plasticity and the hallmarks of cancer (2017, background): “In stem cells, the maintenance of pluripotency is dependent on finely tuned levels of the methyl donor S-adenosylmethionine and the demethylase cofactor a-KG (77, 78).”