| First Author | Ding M | Year | 2018 |
| Journal | J Pineal Res | Volume | 65 |
| Issue | 2 | Pages | e12491 |
| PubMed ID | 29575122 | Mgi Jnum | J:320900 |
| Mgi Id | MGI:6863531 | Doi | 10.1111/jpi.12491 |
| Citation | Ding M, et al. (2018) Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1alpha pathway. J Pineal Res 65(2):e12491 |
| abstractText | Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes-induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes-induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes-induced cardiac dysfunction by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. 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. In high glucose-exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC-1alpha and inhibited Drp1-mediated mitochondrial fission and mitochondria-derived superoxide production. In contrast, SIRT1 or PGC-1alpha siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1-mediated mitochondrial fission in a SIRT1/PGC-1alpha-dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC-1alpha directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi-1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission through SIRT1-PGC1alpha pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes. |
