PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence
- University of Kentucky, United States
- The University of Texas Southwestern Medical Center, United States
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.
Data availability
RNA sequencing gene expression and other source data are provided along with this manuscript.
Article and author information
Author details
Dara Buendia Castillo
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.
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).
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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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
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