1. Cell Biology
  2. Neuroscience
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HIF1α stabilization in hypoxia is not oxidant-initiated

  1. Amit Kumar
  2. Manisha Vaish
  3. Saravanan S Karuppagounder
  4. Irina Gazaryan
  5. John W Cave
  6. Anatoly A Starkov
  7. Elizabeth T Anderson
  8. Sheng Zhang
  9. John T Pinto
  10. Austin M Rountree
  11. Wang Wang
  12. Ian R Sweet
  13. Rajiv R Ratan  Is a corresponding author
  1. Burke Neurological Institute, United States
  2. Regeneron Pharmaceuticals Inc, United States
  3. New York Medical College, United States
  4. InVitro Cell Research, United States
  5. Weill Medical College of Cornell University, United States
  6. Cornell university, United States
  7. University of Washington, United States
Research Article
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Cite this article as: eLife 2021;10:e72873 doi: 10.7554/eLife.72873

Abstract

Hypoxic adaptation mediated by HIF transcription factors requires mitochondria, which have been implicated in regulating HIF1α stability in hypoxia by distinct models that involve consuming oxygen or alternatively converting oxygen into the second messenger peroxide. Here, we use a ratiometric, peroxide reporter, HyPer to evaluate the role of peroxide in regulating HIF1α stability. We show that antioxidant enzymes are neither homeostatically induced nor are peroxide levels increased in hypoxia. Additionally, forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Moreover, decrease in lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD, failed to influence HIF1α protein stability. These data show that mitochondrial, cytosolic or lipid ROS were not necessary for HIF1α stability, and favor a model where mitochondria contribute to hypoxic adaptation as oxygen consumers.

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All data generated or analysed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Amit Kumar

    Neuroscience, Burke Neurological Institute, White Plains, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5017-9887
  2. Manisha Vaish

    Muscle and Metabolism, Regeneron Pharmaceuticals Inc, Tarrytown, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Saravanan S Karuppagounder

    Neuroscience, Burke Neurological Institute, White Plains, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Irina Gazaryan

    Department of Anatomy and Cell Biology, New York Medical College, Valhalla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. John W Cave

    Neuroscience, InVitro Cell Research, Englewood, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Anatoly A Starkov

    Brain and Mind Research Institute and Department of Neurology, Weill Medical College of Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Elizabeth T Anderson

    Cornell university, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sheng Zhang

    Cornell university, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8206-1007
  9. John T Pinto

    Department of Anatomy and Cell Biology, New York Medical College, Valhalla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Austin M Rountree

    University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Wang Wang

    University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Ian R Sweet

    University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7565-1663
  13. Rajiv R Ratan

    Neuroscience, Burke Neurological Institute, White Plains, United States
    For correspondence
    rrr2001@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9081-2701

Funding

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

Reviewing Editor

  1. Thilo Hagen

Publication history

  1. Received: August 6, 2021
  2. Accepted: September 19, 2021
  3. Accepted Manuscript published: October 1, 2021 (version 1)

Copyright

© 2021, Kumar 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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