Mitochondrial oxidative stress causes chromosomal instability of mouse embryonic fibroblasts
Open accessAbstract
Reactive oxygen species are an inevitable by-product of mitochondrial respiration. It has been estimated that between 0.4 and 4% of molecular oxygen is converted to the radical superoxide (O2*-) and this level is significantly influenced by the functional status of the mitochondria. It is well established that exogenous oxidative stress and high doses of mitochondrial poisons such as paraquat and carbonyl cyanide 4 (trifluoromethoxy) phenylhydrazone (FCCP) can lead to genomic instability. In this report we show for the first time that endogenous mitochondrial oxidative stress in standard cell culture conditions results in nuclear genomic instability in primary mouse embryonic fibroblasts (MEFs). We show that lack of mitochondrial superoxide dismutase in MEFs leads to a severe increase of double strand breaks, end-to-end fusions, chromosomal translocations, and loss of cell viability and proliferative capacity. Our results predict that endogenous mitochondrial oxidative stress can induce genomic instability, and therefore may have a profound effect in cancer and aging.
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Many kinds of oncogenic or stressful stimuli can induce a senescence response, foremost certain types of DNA damage including DNA breaks and oxidative lesions.
“It is now apparent that many kinds of oncogenic or stressful stimuli can induce a senescence response. Foremost among these are certain types of DNA damage, including DNA breaks and oxidative lesions caused by environmental insults, genetic defects, or endogenous processes (DiLeonardo et al., 1994; Hasty et al., 2003; Samper et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Samper et al., 2003
The section ‘Mitochondrial oxidative stress results in chromosomal aberrations’ (page unavailable) reports that oxidative stress can cause DNA double-strand breaks and that SOD2-null mouse fibroblasts had more chromosome breaks. The growth-results section reports poor growth and cell death in most SOD2-null cultures, but does not establish that their DNA damage induced a senescence response. This paper also does not establish the broader claim about many kinds of oncogenic or stressful stimuli. (LLM, conf=0.84)
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References 32 · Cited by 108
Research works printed but not linked: 1
- Zijlmans JM, Martens UM, Poon SS, Raap AK, Tanke HJ, Ward RK, Lansdorp PM (1997) Telomeres in the mouse have large inter- chromosomal variations in the number of T2AG3 repeats. Proc. Natl Acad. Sci. USA 94, 7423-7428.
- Authors
- Samper, E., Nicholls, D. G., & Melov, S.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Melov, S.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2003-09-11
- Volume
- 2
- Issue
- 5
- Pages
- 277-285
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- OpenAlex
- W1506621956
- Cited by
- 108
- References
- 32
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 7 · 2022: 4 · 2021: 8 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 5 · 2012: 10
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- National Institute on Aging (AG18679, R01AG018679)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- mitochondrial oxidative stress, genomic instability, chromosomal instability, mouse embryonic fibroblasts, superoxide dismutase, reactive oxygen species, mitochondrial respiration, DNA double-strand breaks, chromosomal translocation, cell viability, proliferative capacity, cancer, aging
- MeSH terms
- Animals, Cell Division, Cell Transformation, Neoplastic, Cells, Cultured, Embryo, Mammalian, Female, Fibroblasts, Mitochondria, Oxygen, Pregnancy, Superoxide Dismutase, Translocation, Genetic, Apoptosis, Oxidative Stress, Caspases, Chromosomal Instability, Mice, Caspase 3
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