Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells

Keiyo Takubo, Go Nagamatsu, Chiharu I. Kobayashi, Ayako Nakamura-Ishizu, Hiroshi Kobayashi, Eiji Ikeda, Nobuhito Goda, Yasmeen Rahimi, Randall S. Johnson, Tomoyoshi Soga, Atsushi Hirao, Makoto Suematsu, Toshio Suda

Research output: Contribution to journalArticle

330 Citations (Scopus)

Abstract

Defining the metabolic programs that underlie stem cell maintenance will be essential for developing strategies to manipulate stem cell capacity. Mammalian hematopoietic stem cells (HSCs) maintain cell cycle quiescence in a hypoxic microenvironment. It has been proposed that HSCs exhibit a distinct metabolic phenotype under these conditions. Here we directly investigated this idea using metabolomic analysis and found that HSCs generate adenosine-5′- triphosphate by anaerobic glycolysis through a pyruvate dehydrogenase kinase (Pdk)-dependent mechanism. Elevated Pdk expression leads to active suppression of the influx of glycolytic metabolites into mitochondria. Pdk overexpression in glycolysis-defective HSCs restored glycolysis, cell cycle quiescence, and stem cell capacity, while loss of both Pdk2 and Pdk4 attenuated HSC quiescence, glycolysis, and transplantation capacity. Moreover, treatment of HSCs with a Pdk mimetic promoted their survival and transplantation capacity. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSC quiescence and function.

Original languageEnglish
Pages (from-to)49-61
Number of pages13
JournalCell stem cell
Volume12
Issue number1
DOIs
Publication statusPublished - 2013 Jan 3

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Takubo, K., Nagamatsu, G., Kobayashi, C. I., Nakamura-Ishizu, A., Kobayashi, H., Ikeda, E., Goda, N., Rahimi, Y., Johnson, R. S., Soga, T., Hirao, A., Suematsu, M., & Suda, T. (2013). Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell stem cell, 12(1), 49-61. https://doi.org/10.1016/j.stem.2012.10.011