A Mutation in the SDHC Gene of Complex II Increases Oxidative Stress, Resulting in Apoptosis and Tumorigenesis
Open accessAbstract
Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O2−) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.
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Increased levels of reactive oxygen species have been reported in animal models of SDHC dysfunction.
“increased levels of reactive oxygen species have been reported in animal models of SDHC dysfunction [22–24].”
From A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas (2005) · cites this paper as [22]
Ishii et al. detected increases in superoxide production, along with an increase in tumorigenesis, in cells with a mutated SdhC gene.
“Consistent with this model, Ishii et al. detected increases in superoxide production, along with an increase in tumorigenesis, in cells with a mutated SdhC gene (26).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [26]
Transgenic cell lines with a mutated SdhC gene exhibit increased ROS production and increased tumor formation rates in a nude mouse model.
“Transgenic cell lines with a mutated SdhC gene also exhibit increased ROS production and increased tumor formation rates in a nude mouse model (26).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [26]
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Self-citation
- Authors
- Ishii, T., Yasuda, K., Akatsuka, A., Hino, O., Hartman, P. S., & Ishii, N.
- Affiliations
- 1Department of Molecular Life Science and
- Tokai University (JP)
- Japanese Foundation For Cancer Research (JP)
- Texas Christian University (US)
- Venue
- Cancer Research
- Published
- 2005-01-01
- Volume
- 65
- Issue
- 1
- Pages
- 203-209
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2116622745
- Cited by
- 253
- References
- 55
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 15 · 2020: 9 · 2019: 7 · 2018: 11 · 2017: 11 · 2016: 13 · 2015: 9 · 2014: 21 · 2013: 12 · 2012: 19
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Boehringer Ingelheim Japan
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- succinate dehydrogenase, oxidative stress, apoptosis, carcinogenesis, superoxide, mitochondrial DNA damage, protein carbonylation, caspase-3, mitochondrial membrane potential
- MeSH terms
- 8-Hydroxy-2'-Deoxyguanosine, Amino Acid Sequence, Animals, Bacterial Proteins, Base Sequence, Cloning, Molecular, Deoxyguanosine, Gene Frequency, Humans, Membrane Proteins, Mice, Transgenic, Molecular Sequence Data, Neoplasms, Succinate Dehydrogenase, Superoxides, Polymerase Chain Reaction, Sequence Alignment, Apoptosis, Sequence Homology, Amino Acid, DNA Primers, Oxidative Stress, Caspases, Mice, Caspase 3
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