Hyperoxia-induced Apoptosis Does Not Require Mitochondrial Reactive Oxygen Species and Is Regulated by Bcl-2 Proteins
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Exposure of animals to hyperoxia results in lung injury that is characterized by apoptosis and necrosis of the alveolar epithelium and endothelium. The mechanism by which hyperoxia results in cell death, however, remains unclear. We sought to test the hypothesis that exposure to hyperoxia causes mitochondria-dependent apoptosis that requires the generation of reactive oxygen species from mitochondrial electron transport. Rat1a cells exposed to hyperoxia underwent apoptosis characterized by the release of cytochrome c, activation of caspase-9, and nuclear fragmentation that was prevented by the overexpression of Bcl-X(L.) Murine embryonic fibroblasts from bax(-/-) bak(-/-) mice were resistant to hyperoxia-induced cell death. The administration of the antioxidants manganese (III) tetrakis (4-benzoic acid) porphyrin, ebselen, and N-acetylcysteine failed to prevent cell death following exposure to hyperoxia. Human fibrosarcoma cells (HT1080) lacking mitochondrial DNA (rho(0) cells) that failed to generate reactive oxygen species during exposure to hyperoxia were not protected against cell death following exposure to hyperoxia. We conclude that exposure to hyperoxia results in apoptosis that requires Bax or Bak and can be prevented by the overexpression of Bcl-X(L). The mitochondrial generation of reactive oxygen species is not required for cell death following exposure to hyperoxia.
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Activation of hyperoxia-induced apoptosis factors (Bax) can lead to cell death with or without loss of mitochondrial function.
“Apoptotic factors are also involved in the necrosis of tumor cells under the hyperoxia response, and the activation of hyperoxia‐induced apoptosis factors (Bax) can lead to cell death with or without loss of mitochondrial function (Figure 4B).”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [315]
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- Authors
- Budinger, G. R. S., Tso, M., McClintock, D. S., Dean, D. A., Sznajder, J. I., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Budinger, G. R. Scott
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 277
- Issue
- 18
- Pages
- 15654-15660
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2103430146
- Cited by
- 95
- References
- 40
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2017: 1 · 2016: 2 · 2015: 5 · 2014: 5 · 2013: 3 · 2012: 3
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL67835-01, K08HL067835)
- National Institute of General Medical Sciences (GM-60472, R01GM060472)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- hyperoxia, apoptosis, mitochondrial reactive oxygen species, Bcl-2 family proteins, Bax, Bak, Bcl-xL, cytochrome c release, caspase-9, mitochondrial electron transport chain, oxidative stress, antioxidants, mitochondrial DNA deletions, lung injury, alveolar epithelium, endothelium
- MeSH terms
- Animals, Antimycin A, Cell Line, Cells, Cultured, Fibrosarcoma, Intracellular Membranes, Membrane Potentials, Mitochondria, Tumor Cells, Cultured, Apoptosis, Reactive Oxygen Species, Hyperoxia, Proto-Oncogene Proteins c-bcl-2, Rats
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