Mitochondrial Hormesis and Diabetic Complications

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.

Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

“…Furthermore, studies with DHE demonstrated an enhanced DHE/superoxide response in mitochondrial SOD2-deficient mouse kidneys without any enhanced diabetic kidney disease in SOD2-deficient mice (14). These studies do not support the contention that a primary stimulation of mitochondrial superoxide is necessary for subsequent reduction of mitochondrial ETC activity (52). Similar data and conclusions were provided in studies with diabetic neuropathy by Fernyhough's group (5,6,16).…”

The Warburg Effect in Diabetic Kidney Disease

“…57 Based on the new evidence, the theory of "mitochondrial hormesis" has been proposed wherein optimal levels of ROS are considered a marker for functional mitochondria. 85 In steptozotocin-induced and Akita type 1 diabetic mouse models, using a combination of in vivo real-time imaging and electron paramagnetic resonance approaches, we reported that diabetic kidneys have reduced overall ${\mathrm{O}}_2^{-}$ along with a reduction in mitochondrial function, PDH activity, and mitochondrial biogenesis, which all were rescued with activation of AMPK using an AMPK activator. 23 A persistent reduction in mitochondrial oxidative phosphorylation can lead to a reduction in mitochondrial superoxide and a simultaneous activation of cytosolic oxidative pathways triggering cytosolic ROS, resulting in increased oxidative stress.…”

The Tubulointerstitial Pathophysiology of Progressive Kidney Disease

“…92 The decrease in mitochondria further decreases ATP generation. While the source of intracellular ROS remains somewhat controversial, 101–103 one downstream mediator of ROS actions is the stabilization and generation of HIF , which promotes extracellular matrix expression 50 and decreases cell metabolic rates further. With decreased tubular function, less local generation of pro-angiogenic factors such as VEGF leads to decreased health of the peritubular vasculature, 104 further promoting hypoxia and HIF expression.…”