Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Shanjie Wang, Zhijing Zhao, Xinyu Feng, Zheng Cheng, Zhenyu Xiong, Tingting Wang, Jie Lin, Mingming Zhang, Jianqiang Hu, Yanhong Fan, Russel J Reiter, Haichang Wang, Dongdong Sun

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG-treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up-regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20-like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin-mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

Original languageEnglish (US)
Pages (from-to)5132-5144
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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Keywords

  • diabetic cardiomyopathy
  • mammalian Ste20-like kinase 1, Mst1
  • melatonin
  • mitochondrion
  • mitophagy
  • parkin

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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