Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes

Abstract

It 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 β 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.

Effects of Moringa oleifera Leaves Extract on High Glucose-Induced Metabolic Changes in HepG2 Cells

“…Our data is contrasting with previous findings where the content of SIRT3 was heavily decreased in diabetic pancreas and lung [ 53 ], possibly the alterations in SIRT3 in diabetes are likely tissue dependent [ 54 ]. Moreover, when total mitochondrial protein acetylation profile was assessed by anti-acetylation western blot analysis, an increased acetylation on numerous proteins could be detected in diabetes [ 55 ], which corresponds with our results ( Figure 6 b).…”

Redox imbalance stress in diabetes mellitus: Role of the polyol pathway

“…As glucose flux through the polyol pathway consumes NADPH, it has been suggested that the level of NADPH could be significantly decreased . Indeed, we have found that this is the case in diabetic lung and pancreas, whereby NADPH content is lower than that in controls. It has been established that there is about a 15% decrease in NADPH in the diabetic lens .…”

“…So when NAD + levels decrease during diabetes, sirtuin activities will be decreased, and this can also be modulated by decreased expression of sirtuin proteins. Indeed, numerous studies including ours, have demonstrated attenuated expression of sirtuin proteins in diabetes . As a consequence, protein acetylation is increased (Figure A), leading to functional changes of numerous proteins .…”

Streptozotocin-Induced Adaptive Modification of Mitochondrial Supercomplexes in Liver of Wistar Rats and the Protective Effect ofMoringa oleiferaLam

“…In addition, it was found that defective complex I produces more ROS [ 96 ], suggesting that structural modifications of the enzyme may play a crucial role in ROS production process. Recently, it was reported that pancreatic mitochondrial complex I showed aberrant hyperactivity in type 1 and 2 STZ-diabetic mice and rat and in cultured β cells [ 97 ]. Further experiments focusing on STZ-induced diabetes in rats revealed that complex I′s hyperactivity could be attenuated by metformin.…”