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

Cell Stem Cell. 2013 Jan 3;12(1):49-61. doi: 10.1016/j.stem.2012.10.011.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cells, Cultured
  • Flow Cytometry
  • Glycolysis / genetics
  • Glycolysis / physiology*
  • Hematopoietic Stem Cells / metabolism*
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Models, Biological
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Reactive Oxygen Species / metabolism

Substances

  • Pdk2 protein, mouse
  • Pdk4 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Reactive Oxygen Species
  • Protein-Serine-Threonine Kinases