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Cited by 168Cancer, Hypoxia, and MetabolismRedox biology and oxidative stressNitric Oxide and Endothelin Effects

A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression

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Liu, Qing, Berchner-Pfannschmidt, Utta, Möller, Ulrike, Brecht, Martina, Wotzlaw, Christoph, Acker, Helmut, Jungermann, Kurt, Kietzmann, Thomas·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0400265101PMC PMC384736
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Abstract

It has been proposed that hydroxyl radicals (·OH) generated in a perinuclear iron-dependent Fenton reaction are involved in O 2 -dependent gene expression. Thus, it was the aim of this study to localize the cellular compartment in which the Fenton reaction takes place and to determine whether scavenging of ·OH can modulate hypoxia-inducible factor 1 (HIF-1)-dependent gene expression. The Fenton reaction was localized by using the nonfluorescent dihydrorhodamine (DHR) 123 that is irreversibly oxidized to fluorescent rhodamine 123 while scavenging ·OH together with gene constructs allowing fluorescent labeling of mitochondria, endoplasmic reticulum (ER), Golgi apparatus, peroxisomes, or lysosomes. A 3D two-photon confocal laser scanning microscopy showed ·OH generation in distinct hot spots of perinuclear ER pockets. This ER-based Fenton reaction was strictly pO 2 -dependent. Further colocalization experiments showed that the O 2 -sensitive transcription factor HIF-1α was present at the ER under normoxia, whereas HIF-1α was present only in the nucleus under hypoxia. Inhibition of the Fenton reaction by the ·OH scavenger DHR attenuated HIF-prolyl hydroxylase activity and interaction with von Hippel–Lindau protein, leading to enhanced HIF-1α levels, HIF-1α transactivation, and activated expression of the HIF-1 target genes plasminogen activator inhibitor 1 and heme oxygenase 1. Further, ·OH scavenging appeared to enhance redox factor 1 (Ref-1) binding and, thus, recruitment of p300 to the transactivation domain C because mutation of the Ref-1 binding site cysteine 800 abolished DHR-induced transactivation. Thus, the localized Fenton reaction appears to impact the expression of hypoxia-regulated genes by means of HIF-1α stabilization and coactivator recruitment.

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  • Fenton chemistry and hydroxyl radical formation influence ROS propagation and the availability of catalytically active Fe2+ required for PHD function.

    “Fenton chemistry and hydroxyl radical formation influence both ROS propagation and the availability of catalytically active Fe2+ required for PHD function.”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [209]

    The Abstract gives the Fenton reaction as H2O2 + Fe2+ → Fe3+ + hydroxyl radical, and the Discussion says prolyl hydroxylase activity depends on Fe2+ and was inhibited when hydroxyl radicals were scavenged. The paper also discusses intracellular ROS turnover, but it does not establish that Fenton chemistry influences ROS propagation or demonstrate a change in the availability of catalytically active Fe2+ for prolyl hydroxylase. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Perturbations in iron redox cycling intersect directly with HIF hydroxylation chemistry, linking mitochondrial metabolism, oxidative reactions, and enzymatic HIF control into a unified redox framework.

    “Perturbations in iron redox cycling (driven by oxidative stress, chelation, or metabolic remodeling), therefore intersect directly with HIF hydroxylation chemistry, linking mitochondrial metabolism, oxidative reactions, and enzymatic HIF control into a unified redox framework [209].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [209]

    The Discussion (page not provided) links an Fe2+-dependent Fenton reaction to HIF-1α prolyl hydroxylase activity and VHL binding, supporting the iron-redox and enzymatic-HIF connection. But it locates the reaction at the ER, not mitochondria, and says an operating mitochondrial respiratory chain is not involved in the ROS generation studied. The supplied passages do not establish chelation or metabolic remodeling as drivers of this mechanism. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Liu, Q., Berchner-Pfannschmidt, U., Möller, U., Brecht, M., Wotzlaw, C., Acker, H., Jungermann, K., & Kietzmann, T.
Affiliations
  • Max Planck Society (DE)
  • Institut für Biochemie und Molekulare Zellbiologie, Humboldtallee 23, D-37073 Göttingen, Germany; and Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-03-09
Volume
101
Issue
12
Pages
4302-4307
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0400265101
PMC
PMC384736
OpenAlex
W2046018661
Cited by
168
References
42
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 1 · 2019: 6 · 2018: 5 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 7 · 2012: 6
FWCI
5.85
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
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
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
Fenton reaction, endoplasmic reticulum, hydroxyl radicals, HIF-1, HIF-1α, HIF-1α stabilization, von Hippel-Lindau protein, redox factor-1, p300 coactivator, hypoxia-inducible gene expression, plasminogen activator inhibitor-1, heme oxygenase-1, dihydrorhodamine 123, oxidative stress
MeSH terms
Hypoxia, Cell Nucleus, Endoplasmic Reticulum, Gene Expression Regulation, Humans, Oxidation-Reduction, Rhodamines, Transcription Factors, Genes, Reporter, Rhodamine 123, Hypoxia-Inducible Factor 1, alpha Subunit, In Vitro Techniques

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