PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence

Abstract

Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mitochondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PASK, resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity, and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK.

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RNA sequencing gene expression and other source data are provided along with this manuscript.

Article and author information

Author details

  1. Michael Xiao

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Chia-Hua Wu

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5361-5469
  3. Graham Meek

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Brian Kelly

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Dara Buendia Castillo

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8955-2984
  6. Lyndsay EA Young

    Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sara Martire

    Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sajina Dhungel

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Elizabeth McCauley

    Department of Biology, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Purbita Saha

    Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Altair L Dube

    Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Matthew S Gentry

    Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5253-9049
  13. Laura A Banaszynski

    Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Ramon C Sun

    Molecular and Cellular Biochemistry, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3009-1850
  15. Chintan K Kikani

    Department of Biology, University of Kentucky, Lexington, United States
    For correspondence
    chintan.kikani@uky.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1140-0192

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R01AR073906-01A1)

  • Chintan K Kikani

National Cancer Institute (AG066653-01)

  • Ramon C Sun

National Institute of General Medical Sciences (GM124958)

  • Laura A Banaszynski

National Cancer Institute (F99CA264165)

  • Lyndsay EA Young

American Cancer Society (134230-RSG-20-043-01)

  • Laura A Banaszynski

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD109239)

  • Laura A Banaszynski

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Apurva Sarin, Institute for Stem Cell Science and Regenerative Medicine, India

Ethics

Animal experimentation: Muscle Injury and Regeneration Animal experiments were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee at the University of Kentucky to CK (2019-3317).

Version history

  1. Preprint posted: March 25, 2022 (view preprint)
  2. Received: July 8, 2022
  3. Accepted: April 11, 2023
  4. Accepted Manuscript published: April 13, 2023 (version 1)
  5. Version of Record published: May 5, 2023 (version 2)

Copyright

© 2023, Xiao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Michael Xiao
  2. Chia-Hua Wu
  3. Graham Meek
  4. Brian Kelly
  5. Dara Buendia Castillo
  6. Lyndsay EA Young
  7. Sara Martire
  8. Sajina Dhungel
  9. Elizabeth McCauley
  10. Purbita Saha
  11. Altair L Dube
  12. Matthew S Gentry
  13. Laura A Banaszynski
  14. Ramon C Sun
  15. Chintan K Kikani
(2023)
PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence
eLife 12:e81717.
https://doi.org/10.7554/eLife.81717

Share this article

https://doi.org/10.7554/eLife.81717

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