Melatonin, chemically N-acetyl-5-methoxytryptamine, has been proved to exert its protective properties in a variety of cardiovascular diseases. 10 However, whether inhibition of mitochondrial fission is efficient to protect against diabetes-induced cardiac dysfunction is still largely unknown. 9 Moreover, myocardial contractile dysfunction is associated with an increase in mitochondrial fission among diabetic patients. 7, 8 Increased mitochondrial fission was observed in several types of cultured cells from the cardiovascular system under prolonged hyperglycemic conditions. In contrast, excessive mitochondrial fission seems to be detrimental because it is associated with decreased mitochondrial function and increased ROS. 6 Mitochondrial fusion is considered to be beneficial because it is associated with an increase in the mitochondrial function and ATP production. Recent work has highlighted the important role of mitochondrial fusion/fission dynamics in mitochondrial homeostasis. 4, 5 Mitochondria are critical organelles for ROS generation and energy production in cardiomyocytes. Mounting evidence from current studies has indicated that the generation of reactive oxygen species (ROS) contributes to the progression of diabetes-induced cardiac dysfunction. 3 Multiple factors are responsible for the pathogenesis of DCM. 2 Diabetic cardiomyopathy (DCM) is one major complication in diabetics, which impairs myocardial performance even without coronary artery disease or hypertension. The prevalence of diabetes mellitus appears to increase rapidly during recent years in the world, currently estimated at 11.6% in China 1 and 8.3% in America. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes. These findings show that melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission through SIRT1-PGC1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi-1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. Moreover, chromatin immunoprecipitation analysis revealed that PGC-1α directly regulated the expression of Drp1 by binding to its promoter. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1-mediated mitochondrial fission in a SIRT1/PGC-1α-dependent manner. In contrast, SIRT1 or PGC-1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. In high glucose-exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC-1α and inhibited Drp1-mediated mitochondrial fission and mitochondria-derived superoxide production. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ)-induced diabetic mice, but not in SIRT1 −/− diabetic mice. Here, we show that melatonin prevented diabetes-induced cardiac dysfunction by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. This study investigated whether melatonin protects against diabetes-induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. However, whether mitochondrial fission directly promotes diabetes-induced cardiac dysfunction is still unknown. Mitochondrial division is important for the #remodeling and rearrangement of mitochondrial networks, as well as for enabling mitochondrial segregation during cell division.Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. Mitochondria divide by simple fission, splitting in two just as bacterial cells do, and although the DNA replication strategies are a little different, forming displacement or D-loop structures, they partition their circular DNA in much the same way as do bacteria. #Miochondria #fusion and #fission #Gtpases #lifecycleofmitochondria #Drp1 #OPA1 #cellbiology #cellorganellies
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