HIF1α stabilization in hypoxia is not oxidant-initiated
- Burke Neurological Institute, United States
- Regeneron Pharmaceuticals Inc, United States
- New York Medical College, United States
- InVitro Cell Research, United States
- Weill Medical College of Cornell University, United States
- Cornell university, United States
- University of Washington, United States
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.
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Funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Thilo Hagen
Version history
- Received: August 6, 2021
- Accepted: September 19, 2021
- Accepted Manuscript published: October 1, 2021 (version 1)
- Version of Record published: October 21, 2021 (version 2)
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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HIF1α stabilization in hypoxia is not oxidant-initiated
eLife 10:e72873.
https://doi.org/10.7554/eLife.72873
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