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CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life
Abstract
Mice deficient in CuZn superoxide dismutase (CuZnSOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1-/- mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1-/- and age-matched +/+ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1-/- mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.
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“For example, mice deficient in either Cu-ZnSOD or MnSOD have widespread oxidative damage and hepatocarcinogenesis or neurodegeneration with reduced lifespan (Elchuri et al., 2005; Lebovitz et al., 1996).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Elchuri et al., 2005
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Metadata
- Authors
- Elchuri, S., Oberley, T. D., Qi, W., Eisenstein, R. S., Jackson Roberts, L., Van Remmen, H., Epstein, C. J., & Huang, T.-T.
- Affiliations
- Stanford University (US)
- University of Wisconsin–Madison (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, San Francisco (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Huang, Ting-Ting
- Venue
- Oncogene
- Published
- 2004-11-08
- Volume
- 24
- Issue
- 3
- Pages
- 367-380
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2042637324
- Cited by
- 667
- References
- 72
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 24 · 2023: 27 · 2022: 32 · 2021: 25 · 2020: 24 · 2019: 24 · 2018: 25 · 2017: 31 · 2016: 29 · 2015: 35 · 2014: 48 · 2013: 48 · 2012: 45
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG16998, R01AG016998, R01AG016633, AG16633)
- National Institute of General Medical Sciences (GM 15431, GM 42056)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-26657, DK47219, P30DK026657)
- Topics
- 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
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- Cu/Zn superoxide dismutase, Sod1 knockout mice, hepatocarcinogenesis, oxidative damage, liver nodules, hepatocellular carcinoma, nodular hyperplasia, aconitase, 8-oxoguanine, F2-isoprostanes, glutathione peroxidase, Mn superoxide dismutase, carbonic anhydrase III, APEX1, DNA repair, cyclin D1, cyclin D3, c-Met, hepatocyte proliferation, aging
- MeSH terms
- Aging, Animals, Cell Nucleus, Liver, Liver Neoplasms, Mitochondria, Superoxide Dismutase, Mice, Knockout, Oxidative Stress, Mice
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