Lack of the DNA glycosylases MYH and OGG1 in the cancer prone double mutant mouse does not increase mitochondrial DNA mutagenesis
Abstract
Reactive oxygen species (ROS) are formed as natural byproducts during aerobic metabolism and readily induce premutagenic base lesions in the DNA. The 8-oxoguanine DNA glycosylase (OGG1) and MutY homolog 1 (MYH) synergistically prevent mutagenesis and cancer formation in mice. Their localization in the mitochondria as well as in the nucleus suggests that mutations in mitochondrial DNA (mtDNA) contribute to the carcinogenesis in the myh⁻/⁻/ogg1⁻/⁻ double knockout mouse. In order to test this hypothesis, we analyzed mtDNA mutagenesis and mitochondrial function in young (1month) and adult (6months) wt and myh⁻/⁻/ogg1⁻/⁻ mice. To our surprise, the absence of OGG1 and MYH had no impact on mtDNA mutation rates in these mice, even at the onset of cancer. This indicates that mtDNA mutagenesis is not responsible for the carcinogenesis of myh⁻/⁻/ogg1⁻/⁻ mice. In line with these results, mitochondrial function was unaffected in the cancerous tissues liver and lung, whereas a significant reduction in respiration capacity was observed in brain mitochondria from the adult myh⁻/⁻/ogg1⁻/⁻ mouse. The reduced respiration capacity correlated with a specific reduction (-25%) in complex I biochemical activity in brain mitochondria. Our results demonstrate that mtDNA mutations are not associated with cancer development in myh⁻/⁻/ogg1⁻/⁻ mice, and that impairment of mitochondrial function in brain could be linked to nuclear DNA mutations in this strain. OGG1 and MYH appear to be dispensable for antimutator function in mitochondria.
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ogg1 or ogg1/mth1 knock-out mice have 20-fold higher levels of 8-oxoguanine in mtDNA and half the life expectancy relative to wild-type mice, but no increase in mtDNA mutations.
“The ogg1 or ogg1/mth1 knock-out mice have 20-fold higher levels of 8-oxoguanine in mtDNA (de Souza-Pinto et al., 2001) and half the life expectancy relative to wild-type (WT) mice (Xie et al., 2004), but no increase in mtDNA mutations (Halsne et al., 2012).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Halsne et al., 2012
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- Authors
- Halsne, R., Esbensen, Y., Wang, W., Scheffler, K., Suganthan, R., Bjørås, M., & Eide, L.
- Affiliations
- Oslo University Hospital (NO)
- Akershus University Hospital (NO)
- Corresponding author
- Eide, Lars
- Venue
- DNA repair
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 11
- Issue
- 3
- Pages
- 278-285
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- OpenAlex
- W1978171259
- Cited by
- 39
- References
- 40
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 4 · 2014: 4 · 2013: 2 · 2012: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- MUTYH, OGG1, carcinogenesis, reactive oxygen species, 8-oxoguanine, mitochondrial respiration, complex I activity, brain mitochondria
- MeSH terms
- Animals, DNA Damage, DNA, Mitochondrial, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Neoplasms, Organ Specificity, Mutagenesis, Cell Respiration, DNA Glycosylases, Mice, Mutation Rate
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