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

    281 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

    Fingerprint

    Glycolysis
    Hematopoietic Stem Cells
    Cell Cycle Checkpoints
    Stem Cells
    Cell Cycle
    Transplantation
    Metabolomics
    pyruvate dehydrogenase (acetyl-transferring) kinase
    Mitochondria
    Adenosine Triphosphate
    Maintenance
    Phenotype

    ASJC Scopus subject areas

    • Cell Biology
    • Molecular Medicine
    • Genetics

    Cite this

    Takubo, K., Nagamatsu, G., Kobayashi, C. I., Nakamura-Ishizu, A., Kobayashi, H., Ikeda, E., ... 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

    Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. / Takubo, Keiyo; Nagamatsu, Go; Kobayashi, Chiharu I.; Nakamura-Ishizu, Ayako; Kobayashi, Hiroshi; Ikeda, Eiji; Goda, Nobuhito; Rahimi, Yasmeen; Johnson, Randall S.; Soga, Tomoyoshi; Hirao, Atsushi; Suematsu, Makoto; Suda, Toshio.

    In: Cell Stem Cell, Vol. 12, No. 1, 03.01.2013, p. 49-61.

    Research output: Contribution to journalArticle

    Takubo, K, Nagamatsu, G, Kobayashi, CI, Nakamura-Ishizu, A, Kobayashi, H, Ikeda, E, Goda, N, Rahimi, Y, Johnson, RS, 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, vol. 12, no. 1, pp. 49-61. https://doi.org/10.1016/j.stem.2012.10.011
    Takubo, Keiyo ; Nagamatsu, Go ; Kobayashi, Chiharu I. ; Nakamura-Ishizu, Ayako ; Kobayashi, Hiroshi ; Ikeda, Eiji ; Goda, Nobuhito ; Rahimi, Yasmeen ; Johnson, Randall S. ; Soga, Tomoyoshi ; Hirao, Atsushi ; Suematsu, Makoto ; Suda, Toshio. / Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. In: Cell Stem Cell. 2013 ; Vol. 12, No. 1. pp. 49-61.
    @article{4565c5dbbbaf4c5ead1b93c5e1ae45bf,
    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.",
    author = "Keiyo Takubo and Go Nagamatsu and Kobayashi, {Chiharu I.} and Ayako Nakamura-Ishizu and Hiroshi Kobayashi and Eiji Ikeda and Nobuhito Goda and Yasmeen Rahimi and Johnson, {Randall S.} and Tomoyoshi Soga and Atsushi Hirao and Makoto Suematsu and Toshio Suda",
    year = "2013",
    month = "1",
    day = "3",
    doi = "10.1016/j.stem.2012.10.011",
    language = "English",
    volume = "12",
    pages = "49--61",
    journal = "Cell Stem Cell",
    issn = "1934-5909",
    publisher = "Cell Press",
    number = "1",

    }

    TY - JOUR

    T1 - Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells

    AU - Takubo, Keiyo

    AU - Nagamatsu, Go

    AU - Kobayashi, Chiharu I.

    AU - Nakamura-Ishizu, Ayako

    AU - Kobayashi, Hiroshi

    AU - Ikeda, Eiji

    AU - Goda, Nobuhito

    AU - Rahimi, Yasmeen

    AU - Johnson, Randall S.

    AU - Soga, Tomoyoshi

    AU - Hirao, Atsushi

    AU - Suematsu, Makoto

    AU - Suda, Toshio

    PY - 2013/1/3

    Y1 - 2013/1/3

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84872011926&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84872011926&partnerID=8YFLogxK

    U2 - 10.1016/j.stem.2012.10.011

    DO - 10.1016/j.stem.2012.10.011

    M3 - Article

    C2 - 23290136

    AN - SCOPUS:84872011926

    VL - 12

    SP - 49

    EP - 61

    JO - Cell Stem Cell

    JF - Cell Stem Cell

    SN - 1934-5909

    IS - 1

    ER -