Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway

被引:430
作者
Ding, Mingge [1 ,2 ]
Feng, Na [3 ]
Tang, Daishi [4 ]
Feng, Jiahao [3 ]
Li, Zeyang [3 ]
Jia, Min [3 ]
Liu, Zhenhua [3 ]
Gu, Xiaoming [3 ]
Wang, Yuemin [3 ]
Fu, Feng [3 ]
Pei, Jianming [3 ]
机构
[1] Xi An Jiao Tong Univ, Xian Cent Hosp, Dept Cardiol, Xian, Shaanxi, Peoples R China
[2] Xi An Jiao Tong Univ, Xian Cent Hosp, Dept Geriatr, Xian, Shaanxi, Peoples R China
[3] Fourth Mil Med Univ, Sch Basic Med, Natl Key Discipline Cell Biol, Dept Physiol, Xian, Shaanxi, Peoples R China
[4] Dalian Univ, Affiliated Zhongshan Hosp, Dept Endocrinol, Dalian, Peoples R China
基金
中国国家自然科学基金;
关键词
diabetes; Drp1; melatonin; mitochondrial fission; PGC-1; alpha; silent information regulator 1; ISCHEMIA-REPERFUSION INJURY; DYNAMIN-RELATED PROTEIN-1; CONTRACTILE DYSFUNCTION; OXIDATIVE STRESS; PROTECTS; INHIBITION; SIRT1; MECHANISMS; APOPTOSIS; RATS;
D O I
10.1111/jpi.12491
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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-1 alpha and inhibited Drp1-mediated mitochondrial fission and mitochondria-derived superoxide production. In contrast, SIRT1 or PGC-1 alpha 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-1 alpha-dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC-1 alpha 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-PGC1 alpha 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.
引用
收藏
页数:16
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