Redox imbalance and aberrant mitochondrial enzymatic activities in diabetic lung

dc.contributor.authorJin, Zhen
dc.contributor.authorYan, Liang-Jun
dc.creatorWu, Jinzi
dc.description.abstractThe lung is a known target of diabetic injury, but the underlying mechanisms of damage remains poorly understood. We hypothesized that pulmonary cellular redox imbalance and mitochondrial abnormalities contribute to diabetic lung injury. To test this hypothesis, we induced diabetes in rats by streptozotocin and measured redox imbalance parameters including aldose reductase activity, poly ADP ribose polymerase (PARP) activation, NAD+ and NADPH contents along with mitochondrial functional parameters represented by the enzymatic activities of complexes I to IV. Results indicate that aldose reductase activity was elevated and PARP was upregulated in diabetic lung, while the contents of both NAD+ and NADPH were decreased in diabetic lung, demonstrating an excess NADH-linked redox imbalance problem in diabetic lung. Consequently, the enzymatic activities of complexes I to IV were all elevated in diabetic lung mitochondria due to an NADH oversupply. We also found that the enzymatic activities of dihydrolipoamide dehydrogenase (DLDH) and mitochondrial sirtuin 3 (Sirt3), both of which are inducible enzymes and are NAD+-dependent, were impaired in diabetic lung, and such an impairment was due to a decreased level of protein expression for both DLDH and Sirt3. For DLDH functional impairment in diabetic lung, protein acetylation also appeared to play a role as DLDH acetylation was increased. Additionally, we found that an increased complex I activity in diabetic pulmonary mitochondria was partly due to hyperglycemia-induced upregulation of nicotinamide N-methyltransferase (NNMT) and a concomitant increase in the expression of NDUFS3, a complex I subunit that is responsible for complex I assembly. The overall outcome of this NADH-driven redox imbalance and aberrant mitochondrial enzyme functions were a decreased ATP content, an increased NAD(P)H dehydrogenase, quinone 1 (NQO1) activity, and an elevated hydrogen peroxide concentration that reflects an aggravated oxidative stress. These findings demonstrate that diabetic lung exhibits NADH/NAD+-linked redox imbalance and abnormal mitochondrial function that likely contribute to energy deficiency and oxidative damage involved in diabetic lung injury.
dc.titleRedox imbalance and aberrant mitochondrial enzymatic activities in diabetic lung