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DrΓΆse S, Hanley PJ, Brandt U (2009) Ambivalent effects of diazoxide on mitochondrial ROS production at respiratory chain complexes I and III. Biochim. Biophys. Acta 1790: 558-565. |
Droese S, Hanley PJ, Brandt U (2009) Biochim. Biophys. Acta
Abstract: Background
Reactive oxygen species (ROS) are among the main determinants of cellular damage during ischemia and reperfusion. There is also ample evidence that mitochondrial ROS production is involved in signaling during ischemic and pharmacological preconditioning. In a previous study we analyzed the mitochondrial effects of the efficient preconditioning drug diazoxide and found that it increased the mitochondrial oxidation of the ROS-sensitive fluorescent dye 2β²,7β²-dichlorodihydrofluorescein (H2DCF) but had no direct impact on the H2O2 production of submitochondrial particles (SMP) or intact rat heart mitochondria (RHM).
Methods
H2O2 generation of bovine SMP and tightly coupled RHM was monitored under different conditions using the amplex red/horseradish peroxidase assay in response to diazoxide and a number of inhibitors.
Results
We show that diazoxide reduces ROS production by mitochondrial complex I under conditions of reverse electron transfer in tightly coupled RHM, but stimulates mitochondrial ROS production at the Qo site of complex III under conditions of oxidant-induced reduction; this stimulation is greatly enhanced by uncoupling. These opposing effects can both be explained by inhibition of complex II by diazoxide. 5-Hydroxydecanoate had no effect, and the results were essentially identical in the presence of Na+ or K+ excluding a role for putative mitochondrial KATP-channels.
General significance
A straightforward rationale is presented to mechanistically explain the ambivalent effects of diazoxide reported in the literature. Depending on the metabolic state and the membrane potential of mitochondria, diazoxide-mediated inhibition of complex II promotes transient generation of signaling ROS at complex III (during preconditioning) or attenuates the production of deleterious ROS at complex I (during ischemia and reperfusion). β’ Keywords: Mitochondria, Reactive oxygen species, Diazoxide, Pharmacological preconditioning, Respiratory chain, Redox signaling
β’ O2k-Network Lab: DE_Frankfurt_Brandt U
Labels:
Stress:RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property. Organism: Rat, Other Mammal"Other Mammal" is not in the list (Human, Pig, Mouse, Rat, Guinea pig, Bovines, Horse, Dog, Rabbit, Cat, ...) of allowed values for the "Mammal and model" property. Tissue;cell: Cardiac Muscle"Cardiac Muscle" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property. Preparation: Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property., SMP Enzyme: Complex I, Complex III Regulation: Respiration; OXPHOS; ETS Capacity"Respiration; OXPHOS; ETS Capacity" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.
HRR: Oxygraph-2k