title: Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells.
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.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinano-machi, Shinjuku-ku, Tokyo, Japan. keiyot@gmail.com
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Go
authors.initials: G
authors.lastname: Nagamatsu
authors.forename: Chiharu I
authors.initials: CI
authors.lastname: Kobayashi
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakamura-Ishizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Goda
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D006019:Glycolysis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C000631435:Pdk2 protein, mouse; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D017346:Protein Serine-Threonine Kinases