Redox imbalance and mitochondrial abnormalities in the diabetic lung

Abstract

Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD+ redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD+ content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD+ dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD+ redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes.

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 .…”

“…This can tilt the redox balance between NADH and NAD + toward the side of NADH, resulting in redox imbalance . This is indeed what occurs in diabetes and the polyol pathway is known to play a major role in breaking the redox balance between NADH and NAD + …”

Sirt3-dependent deacetylation of SOD2 plays a protective role against oxidative stress in oocytes from diabetic mice

“…12 ROS produced primarily in the mitochondria as a byproduct of metabolism, and mitochondria are also a vulnerable target of ROS-induced oxidative damage. 28,34 Meanwhile, other reports also showed that ROS mediates oxidative damage that may lead to mitochondrial dysfunction in mammalian oocytes. 34,35 Particularly, mammalian oocytes are very sensitive to oxidative stress.…”

Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury

“…ATP content was measured spectrophotometrically by an ATP probe kit that was purchased from BioVision (Milpitas, CA, catalog# K354–100). This assay employs phosphorylation of glycerol by ATP to yield ADP, and the byproduct of this reaction eventually oxidizes the probe to form resorufin that can be easily monitored at 570 nm [65, 66]. Mitochondrial function measured as mitochondrial respiration was performed using Mito-ID extracellular oxygen sensor kit as previously described [67].…”