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Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene
Open accessAbstract
Oxidative stress resulting from mitochondrially derived reactive oxygen species (ROS) has been hypothesized to damage mitochondrial oxidative phosphorylation (OXPHOS) and to be a factor in aging and degenerative disease. If this hypothesis is correct, then genetically inactivating potential mitochondrial antioxidant enzymes such as glutathione peroxidase-1 (Gpx1; EC 1.11.1.9) should increase mitochondrial ROS production and decrease OXPHOS function. To determine the expression pattern of Gpx1, isoform-specific antibodies were generated and mutant mice were prepared in which the Gpx1 protein was substituted for by beta-galactosidase, driven by the Gpx1 promoter. These experiments revealed that Gpx1 is highly expressed in both the mitochondria and the cytosol of the liver and kidney, but poorly expressed in heart and muscle. To determine the physiological importance of Gpx1, mice lacking Gpx1 were generated by targeted mutagenesis in mouse ES cells. Homozygous mutant Gpx1(tm1Mgr) mice have 20% less body weight than normal animals and increased levels of lipid peroxides in the liver. Moreover, the liver mitochondria were found to release markedly increased hydrogen peroxide, a Gpx1 substrate, and have decreased mitochondrial respiratory control ratio and power output index. Hence, genetic inactivation of Gpx1 resulted in growth retardation, presumably due in part to reduced mitochondrial energy production as a product of increased oxidative stress.
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“Consistent with a role for GPx-1 in modulating mitochondrial oxidants, its deficiency in mice augments release of oxidants from respiring mitochondria (126).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [126]
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Piva, E., Kholdihaghighi, S., Ametrano, A., Schumann, S., Pacchini, S., Cortese, M., Drago, L., Baroni, F., Fogliano, C., Coscia, M. R., et al. (2026) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2026.110509 · Cited by 1
Metadata
- Authors
- Esposito, L. A., Kokoszka, J. E., Waymire, K. G., Cottrell, B., MacGregor, G. R., & Wallace, D. C.
- Affiliations
- Emory University (US)
- Corresponding author
- Wallace, Douglas C.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 28
- Issue
- 5
- Pages
- 754-766
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC3049813
- OpenAlex
- W2002860741
- Cited by
- 228
- References
- 47
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 5 · 2018: 11 · 2017: 7 · 2016: 5 · 2015: 3 · 2014: 8 · 2013: 10 · 2012: 6
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG-13154, R01AG013154)
- National Institute of General Medical Sciences (T32GM008490)
- National Institute of Neurological Disorders and Stroke (NS-21328, R01NS021328)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-36437, R01HD036437)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- glutathione peroxidase 1, mitochondrial oxidative stress, reactive oxygen species, oxidative phosphorylation, hydrogen peroxide, lipid peroxidation, growth retardation, liver mitochondria, respiratory control ratio, mitochondrial energy production, tissue-specific gene expression
- MeSH terms
- Glutathione Peroxidase GPX1, Animals, Base Sequence, Female, Free Radicals, Glutathione Peroxidase, Hydrogen Peroxide, Male, Mice, Inbred C57BL, Mitochondria, Mitochondria, Heart, Mitochondria, Liver, Oxygen Consumption, Pregnancy, DNA Primers, Mice, Knockout, Oxidative Stress, Mice, In Vitro Techniques
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