Browsing by Subject "redox imbalance"
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Item NADH/NAD(+) Redox Imbalance and Diabetic Kidney Disease(MDPI, 2021-05-14) Yan, Liang-JunDiabetic kidney disease (DKD) is a common and severe complication of diabetes mellitus. If left untreated, DKD can advance to end stage renal disease that requires either dialysis or kidney replacement. While numerous mechanisms underlie the pathogenesis of DKD, oxidative stress driven by NADH/NAD(+) redox imbalance and mitochondrial dysfunction have been thought to be the major pathophysiological mechanism of DKD. In this review, the pathways that increase NADH generation and those that decrease NAD(+) levels are overviewed. This is followed by discussion of the consequences of NADH/NAD(+) redox imbalance including disruption of mitochondrial homeostasis and function. Approaches that can be applied to counteract DKD are then discussed, which include mitochondria-targeted antioxidants and mimetics of superoxide dismutase, caloric restriction, plant/herbal extracts or their isolated compounds. Finally, the review ends by pointing out that future studies are needed to dissect the role of each pathway involved in NADH-NAD(+) metabolism so that novel strategies to restore NADH/NAD(+) redox balance in the diabetic kidney could be designed to combat DKD.Item Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes(Elsevier Inc., 2017-07-19) Wu, Jinzi; Luo, Xiaoting; Thangthaeng, Nopporn; Sumien, Nathalie; Chen, Zhenglan; Rutledge, Margaret A.; Jing, Siqun; Forster, Michael J.; Yan, Liang-JunIt is well established that NADH/NAD(+) redox balance is heavily perturbed in diabetes, and the NADH/NAD(+) redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD(+) regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD(+) redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and beta cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti-diabetic therapies.