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Mitochondrial hormesis and diabetic complications - PubMed

Review

Mitochondrial hormesis and diabetic complications

Kumar Sharma. Diabetes. 2015 Mar.

Abstract

The concept that excess superoxide production from mitochondria is the driving, initial cellular response underlying diabetes complications has been held for the past decade. However, results of antioxidant-based trials have been largely negative. In the present review, the data supporting mitochondrial superoxide as a driving force for diabetic kidney, nerve, heart, and retinal complications are reexamined, and a new concept for diabetes complications--mitochondrial hormesis--is presented. In this view, production of mitochondrial superoxide can be an indicator of healthy mitochondria and physiologic oxidative phosphorylation. Recent data suggest that in response to excess glucose exposure or nutrient stress, there is a reduction of mitochondrial superoxide, oxidative phosphorylation, and mitochondrial ATP generation in several target tissues of diabetes complications. Persistent reduction of mitochondrial oxidative phosphorylation complex activity is associated with the release of oxidants from nonmitochondrial sources and release of proinflammatory and profibrotic cytokines, and a manifestation of organ dysfunction. Restoration of mitochondrial function and superoxide production via activation of AMPK has now been associated with improvement in markers of renal, cardiovascular, and neuronal dysfunction with diabetes. With this Perspective, approaches that stimulate AMPK and PGC1α via exercise, caloric restriction, and medications result in stimulation of mitochondrial oxidative phosphorylation activity, restore physiologic mitochondrial superoxide production, and promote organ healing.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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Figures

Figure 1
Figure 1

New evidence-based hypothesis implicating reduced superoxides in diabetes complications. The conventional wisdom views that with excess intracellular glucose exposure there is a consequent increase in pyruvate-mediated stimulation of the TCA cycle leading to increased production of electron donors to drive the ETC and generate superoxide. However, based on new in vivo data from the diabetic kidney and nerve, a counterview suggests that excess intracellular glucose enhances PDH phosphorylation to block pyruvate uptake into mitochondria, which results in reduced activity of the ETC and limits mitochondrial ATP production. The reduced ETC activity will result in less superoxide production—rather than more—in diabetic organs in vivo. Increased glycolytic flux may also be a feature in target organs of diabetes complications.

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