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Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice
Liuji Chen1, Ren Na, Mingjun Gu
1Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas 78229, USA.
Abstract:
H(2)O(2) is a major reactive oxygen species produced by mitochondria that is implicated to be important in aging and pathogenesis of diseases such as diabetes; however, the cellular and physiological roles of mitochondrial H(2)O(2) remain poorly understood. Peroxiredoxin 3 (Prdx3/Prx3) is a thioredoxin peroxidase localized in mitochondria. To understand the cellular and physiological roles of mitochondrial H(2)O(2) in aging and pathogenesis of age-associated diseases, we generated transgenic mice overexpressing Prdx3 (Tg(PRDX3) mice). Tg(PRDX3) mice overexpress Prdx3 in a broad range of tissues, and the Prdx3 overexpression occurs exclusively in the mitochondria. As a result of increased Prdx3 expression, mitochondria from Tg(PRDX3) mice produce significantly reduced amount of H(2)O(2), and cells from Tg(PRDX3) mice have increased resistance to stress-induced cell death and apoptosis. Interestingly, Tg(PRDX3) mice show improved glucose homeostasis, as evidenced by their reduced levels of blood glucose and increased glucose clearance. Tg(PRDX3) mice are also protected against hyperglycemia and glucose intolerance induced by high-fat diet feeding. Our results further show that the inhibition of GSK3 may play a role in mediating the improved glucose tolerance phenotype in Tg(PRDX3) mice. Thus, our results indicate that reduction of mitochondrial H(2)O(2) by overexpressing Prdx3 improves glucose tolerance.
Insights
Mitochondrial hydrogen peroxide (H(2)O(2)) plays a role in aging and diabetes. Overexpressing Peroxiredoxin 3 (Prdx3) in mice reduced H(2)O(2) and improved glucose tolerance, suggesting a therapeutic target.
Area of Science:
- Mitochondrial biology
- Reactive oxygen species
- Metabolic disease research
Background:
- Mitochondrial hydrogen peroxide (H(2)O(2)) is a key reactive oxygen species implicated in aging and diabetes pathogenesis.
- The precise cellular and physiological roles of mitochondrial H(2)O(2) are not fully understood.
- Peroxiredoxin 3 (Prdx3) is a mitochondrial thioredoxin peroxidase.
Purpose of the Study:
- To investigate the roles of mitochondrial H(2)O(2) in aging and age-associated diseases.
- To determine the effects of reducing mitochondrial H(2)O(2) levels through Prdx3 overexpression.
Main Methods:
- Generation of transgenic mice overexpressing Prdx3 exclusively in mitochondria (Tg(PRDX3) mice).
- Analysis of H(2)O(2) production in mitochondria from Tg(PRDX3) mice.
- Assessment of cellular resistance to stress and apoptosis.
- Evaluation of glucose homeostasis, including blood glucose levels and glucose clearance.
- Investigation of protection against diet-induced hyperglycemia and glucose intolerance.
Main Results:
- Tg(PRDX3) mice exhibited significantly reduced mitochondrial H(2)O(2) production.
- Cells from Tg(PRDX3) mice showed enhanced resistance to stress-induced cell death and apoptosis.
- Tg(PRDX3) mice demonstrated improved glucose homeostasis with lower blood glucose and increased glucose clearance.
- These mice were protected against high-fat diet-induced hyperglycemia and glucose intolerance.
- Inhibition of GSK3 was identified as a potential mechanism mediating improved glucose tolerance.
Conclusions:
- Overexpression of Prdx3 in mitochondria reduces H(2)O(2) levels.
- Reduced mitochondrial H(2)O(2) confers resistance to cellular stress and apoptosis.
- Mitochondrial H(2)O(2) reduction via Prdx3 overexpression improves glucose homeostasis and protects against diet-induced metabolic dysfunction.
