1. Cell Biology
  2. Genetics and Genomics
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Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrel neural progenitor cells

  1. Neel S Singhal
  2. Meirong Bai
  3. Evan M Lee
  4. Shuo Luo
  5. Kayleigh R Cook
  6. Dengke K Ma  Is a corresponding author
  1. University of California, San Francisco, United States
Research Article
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Cite this article as: eLife 2020;9:e55578 doi: 10.7554/eLife.55578

Abstract

Many organisms in nature have evolved mechanisms to tolerate severe hypoxia or ischemia, including the hibernation-capable Arctic ground squirrel (AGS). Although hypoxic or ischemia tolerance in AGS involves physiological adaptations, little is known about the critical cellular mechanisms underlying intrinsic AGS cell resilience to metabolic stress. Through cell survival-based cDNA expression screens in neural progenitor cells, we identify a genetic variant of AGS Atp5g1 that confers cell resilience to metabolic stress. Atp5g1 encodes a subunit of the mitochondrial ATP synthase. Ectopic expression in mouse cells and CRISPR/Cas9 base editing of endogenous AGS loci revealed causal roles of one AGS-specific amino acid substitution in mediating cytoprotection by AGS ATP5G1. AGS ATP5G1 promotes metabolic stress resilience by modulating mitochondrial morphological change and metabolic functions. Our results identify a naturally occurring variant of ATP5G1 from a mammalian hibernator that critically contributes to intrinsic cytoprotection against metabolic stress.

Article and author information

Author details

  1. Neel S Singhal

    Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1605-4444
  2. Meirong Bai

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5919-7464
  3. Evan M Lee

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shuo Luo

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kayleigh R Cook

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dengke K Ma

    Physiology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Dengke.Ma@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5619-7485

Funding

National Institute of General Medical Sciences (R01)

  • Dengke K Ma

Pew Charitable Trusts (Pew Scholar Award)

  • Dengke K Ma

David and Lucile Packard Foundation (Fellowship)

  • Dengke K Ma

Innovative Genomics Institute (Curci Scholar Award)

  • Dengke K Ma

American Heart Association (Fellowship Grant)

  • Neel S Singhal

American Heart Association (Fellowship Grant)

  • Meirong Bai

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

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Publication history

  1. Received: January 29, 2020
  2. Accepted: October 8, 2020
  3. Accepted Manuscript published: October 14, 2020 (version 1)

Copyright

© 2020, Singhal 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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