1. Mst1 inhibits Sirt3 expression and contributes to diabetic cardiomyopathy through inhibiting Parkin-dependent mitophagy.
- Author
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Wang, Shanjie, Zhao, Zhijing, Fan, Yanhong, Zhang, Mingming, Feng, Xinyu, Lin, Jie, Hu, Jianqiang, Cheng, Zheng, Sun, Chuang, Liu, Tingting, Xiong, Zhenyu, Yang, Zhi, Wang, Haichang, and Sun, Dongdong
- Subjects
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DIABETIC cardiomyopathy , *WESTERN immunoblotting , *HEART failure , *THERAPEUTICS - Abstract
Mitochondrial dysfunction contributes to heart failure induced mortality in approximately 80% of diabetic patients. Mitophagy degrades defective mitochondria and maintains a healthy mitochondrial population, which is essential for cardiomyocyte survival in diabetic stress. Herein, we determined whether Mst1 regulated mitophagy and investigated the downstream signaling pathway in the development of diabetic cardiomyopathy (DCM). Mst1 deficiency promoted elimination of dysfunctional mitochondria in diabetic cardiomyopathy without affecting mitochondrial biogenesis. Enhanced mitophagy was observed in Mst1 interfering cardiomyocytes subjected to high glucose treatment using 3-Methyladenine and Chloroquine. Consistent with these results, in vivo and in vitro loss of function experiments indicated that Mst1 participated in the development of DCM by inhibiting Parkin-dependent mitophagy. Mst1 deficiency alleviated the detrimental phenotype of DCM. Interestingly, the protective effects of Mst1 knockout on DCM were compromised in diabetic Parkin−/− mice. Mechanistically, Mst1 knockdown significantly enhanced Parkin expression and translocation to the mitochondria, as evidenced by immunofluorescence study and Western blot analysis. Furthermore, Sirt3 deletion abolished the detrimental effects of Mst1 on DCM. Collectively, Mst1 inhibits Sirt3 expression thus participates in the development of DCM by inhibiting cardiomyocyte mitophagy. The mechanism is associated with Parkin inhibition. • Mst1 inhibition upregulates cardiomyocyte mitophagy to prompt the clearance of impaired mitochondria in diabetic mice. • Mst1 plays a crucial role in the progress of diabetic cardiomyopathy through inhibiting Sirt3-Parkin-mitophagy signaling. • Mst1 mainly regulates Parkin-mediated mitophagy in hyperglycemic injury instead of BNIP3, NIX or FUNDC1-dependent pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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