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Cited by 34Cancer, Hypoxia, and MetabolismRedox biology and oxidative stressCell death mechanisms and regulation

HIF1α stabilization in hypoxia is not oxidant-initiated

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Kumar, Amit, Vaish, Manisha, Karuppagounder, Saravanan S, Gazaryan, Irina, Cave, John W, Starkov, Anatoly A, Anderson, Elizabeth T, Zhang, Sheng +5 more·2021·eLife
DOI 10.7554/elife.72873PMC PMC8530508
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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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  • These ROS inhibit prolyl hydroxylase (PHD) activity, leading to HIF-α stabilization at oxygen levels well above anoxia.

    “and that these ROS inhibit prolyl hydroxylase (PHD) activity, leading to HIF-α stabilization at oxygen levels well above anoxia.”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [202]

    The Introduction describes ROS inhibition of HIF PHDs as a proposed model from earlier studies, not the paper’s finding. In the Discussion, the authors conclude instead that HIF1α stabilization during hypoxia does not require peroxide and note evidence that added peroxide does not inhibit HIF PHDs. The copy provides section labels but no page numbers. (LLM, conf=0.89)

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  • HIF regulation by ROS is graded and redox-window-dependent, explaining how HIF signaling can be engaged under mild hypoxia or near-normoxic conditions in metabolically active or oncogenically transformed cells, rather than exhibiting a binary oxygen response.

    “Importantly, this regulation is graded and redox-window–dependent, explaining how HIF signaling can be engaged under mild hypoxia or even near-normoxic conditions in metabolically active or oncogenically transformed cells, rather than exhibiting a binary oxygen response [[201], [202], [203], [204]].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [202]

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  • Moderate reductions in oxygen tension increase mitochondrial superoxide and hydrogen peroxide generation, particularly at respiratory complexes I and III.

    “Subsequent studies revealed that moderate reductions in oxygen tension increase mitochondrial superoxide and hydrogen peroxide generation, particularly at respiratory complexes I and III”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [202]

    The Introduction describes earlier reports of increased mitochondrial ROS during hypoxia and a proposed mechanism at complex III, but does not identify complex I as a site of increased generation. In Results (“Peroxide levels do not increase during hypoxia”; page unavailable), the authors report that mitochondrial peroxide decreased or remained unchanged under hypoxia, contrary to the claimed increase in hydrogen peroxide. (LLM, conf=0.88)

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Authors
Kumar, A., Vaish, M., Karuppagounder, S. S., Gazaryan, I., Cave, J. W., Starkov, A. A., Anderson, E. T., Zhang, S., Pinto, J. T., Rountree, A. M., Wang, W., Sweet, I. R., & Ratan, R. R.
Affiliations
  • Cornell University (US)
  • Burke Neurological Institute, White Plains
  • New York Medical College (US)
  • University of Washington (US)
Corresponding author
Ratan, Rajiv R
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2021-10-01
Volume
10
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.72873
PMC
PMC8530508
OpenAlex
W3204088622
Cited by
34
References
64
Citations by year
2026: 4 · 2025: 7 · 2024: 11 · 2023: 4 · 2022: 8
FWCI
2.49
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Touro Scholar (Touro College) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Dr. Miriam & Sheldon G. Adelson Medical Research Foundation
  • National Institutes of Health (P01 AG14930-15A1)
  • Goldsmith Fellowship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
HIF-1α stabilization, hypoxia, hypoxia adaptation, reactive oxygen species, mitochondrial reactive oxygen species, lipid hydroperoxides, antioxidant enzymes, GPX4, superoxide dismutase, oxygen consumption
MeSH terms
Animals, HeLa Cells, Humans, Male, Mitochondria, Peroxides, Signal Transduction, Cell Hypoxia, Rats, Sprague-Dawley, Mice, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Stability

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