Mitochondrial complex III regulates hypoxic activation of HIF
Abstract
Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxia-inducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer.
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Mitochondrial ROS contribute to HIF-1α accumulation independently of respiratory activity.
“Specifically, mitochondrial ROS contribute to HIF-1α accumulation independently of respiratory activity, highlighting the paradoxical role of mitochondria in regulating hypoxic signaling [369,377].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [377]
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“Specifically, mitochondrial ROS contribute to HIF-1 α accumulation independently of respiratory activity, highlighting the paradoxical role of mitochondria in regulating hypoxic signaling [369,377].”
- Authors
- Klimova, T., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Chandel, N S
- ORCID
- Chandel, N S
- Venue
- Cell Death & Differentiation
- Published
- 2008-01-25
- Volume
- 15
- Issue
- 4
- Pages
- 660-666
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W2056688967
- Cited by
- 433
- References
- 18
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 16 · 2023: 24 · 2022: 24 · 2021: 25 · 2020: 14 · 2019: 14 · 2018: 17 · 2017: 25 · 2016: 18 · 2015: 29 · 2014: 31 · 2013: 29 · 2012: 38
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA123067-01, R01CA123067)
- National Institute of General Medical Sciences (R01GM060472, GM60472-08)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- mitochondrial complex III, hypoxia-inducible factor, HIF activation, reactive oxygen species, oxygen sensing, hypoxia, cancer, ischemia, metabolic adaptation, angiogenesis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adaptation, Physiological, Animals, Hypoxia, Cell Transformation, Neoplastic, Humans, Mitochondria, Neoplasms, Protein Processing, Post-Translational, Electron Transport Complex III, Cell Hypoxia, Reactive Oxygen Species, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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