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Published on: February 7, 2018
Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress
Holly Van Remmen1, Wenbo Qi, Marian Sabia
1Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284-7762, USA. vanremmen@uthscsa.edu
Abstract:
To examine the effect of compound deficiencies in antioxidant defense, we have generated mice (Sod2(+/-)/Gpx1(-/-)) that are deficient in Mn superoxide dismutase (MnSOD) and glutathione peroxidase 1 (Gpx1) by breeding Sod2(+/-) and Gpx1(-/-) mice together. Although Sod2(+/-)/Gpx1(-/-) mice showed a 50% reduction in MnSOD and no detectable Gpx1 activity in either mitochondria or cytosol in all tissues, they were viable and appeared normal. Fibroblasts isolated from Sod2(+/-)/Gpx1(-/-) mice were more sensitive (4- to 6-fold) to oxidative stress (t-butyl hydroperoxide or gamma irradiation) than fibroblasts from wild-type mice, and were twice as sensitive as cells from Sod2(+/-) or Gpx1(-/-) mice. Whole-animal studies demonstrated that survival of the Sod2(+/-)/Gpx1(-/-) mice in response to whole body gamma irradiation or paraquat administration was also reduced compared with that of wild-type, Sod2(+/-), or Gpx1(-/-) mice. Similarly, endogenous oxidative stress induced by cardiac ischemia/reperfusion injury led to greater apoptosis in heart tissue from the Sod2(+/-)/Gpx1(-/-) mice than in that from mice deficient in either MnSOD or Gpx1 alone. These data show that Sod2(+/-)/Gpx1(-/-) mice, deficient in two mitochondrial antioxidant enzymes, have significantly enhanced sensitivity to oxidative stress induced by exogenous insults and to endogenous oxidative stress compared with either wild-type mice or mice deficient in either MnSOD or Gpx1 alone.
Insights
Mice lacking both manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (Gpx1) show increased sensitivity to oxidative stress. This compound deficiency in antioxidant enzymes impacts survival and apoptosis following various oxidative insults.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Antioxidant enzymes are crucial for cellular defense against oxidative stress.
- Manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (Gpx1) are key mitochondrial and cytosolic antioxidant enzymes, respectively.
- Understanding the combined effects of deficiencies in these enzymes is vital for comprehending oxidative stress pathways.
Purpose of the Study:
- To investigate the physiological consequences of combined deficiencies in MnSOD and Gpx1.
- To assess the sensitivity of mice with compound deficiencies in these antioxidant enzymes to both exogenous and endogenous oxidative stress.
- To compare the oxidative stress response in double-deficient mice to that of single-deficient and wild-type mice.
Main Methods:
- Generation of Sod2(+/-)/Gpx1(-/-) mice through genetic breeding.
- Assessment of MnSOD and Gpx1 activity in various tissues.
- Evaluation of fibroblast sensitivity to oxidative stressors (t-butyl hydroperoxide, gamma irradiation).
- Analysis of whole-animal survival following gamma irradiation and paraquat administration.
- Examination of apoptosis in cardiac tissue after ischemia/reperfusion injury.
Main Results:
- Sod2(+/-)/Gpx1(-/-) mice exhibited reduced MnSOD and undetectable Gpx1 activity but were viable.
- Fibroblasts from these mice were 4- to 6-fold more sensitive to oxidative stress than wild-type and twice as sensitive as single-deficient cells.
- Survival rates were significantly lower in Sod2(+/-)/Gpx1(-/-) mice exposed to gamma irradiation or paraquat.
- Cardiac tissue from double-deficient mice showed increased apoptosis following ischemia/reperfusion injury.
Conclusions:
- Compound deficiency in MnSOD and Gpx1 significantly enhances sensitivity to oxidative stress.
- These mice serve as a valuable model for studying the impact of combined antioxidant enzyme dysfunction.
- The findings highlight the critical, synergistic role of MnSOD and Gpx1 in protecting against both exogenous and endogenous oxidative damage.
