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Cell Death Dis. 2018 May 1;9(5):556. doi: 10.1038/s41419-018-0579-9.

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation.

Yang F1,2,3, Wu R1,2, Jiang Z1,2,3, Chen J1,2,4, Nan J1,2, Su S1,2, Zhang N1,2, Wang C1,2, Zhao J1,2, Ni C1,2, Wang Y1,2, Hu W1,2, Zeng Z1,2, Zhu K1,2, Liu X1,2, Hu X1,2, Zhu W1,2, Yu H1,2, Huang J5, Wang J6,7.

Author information

1
Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.
2
Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
3
Department of Cardiology, Guizhou Provincial People's Hospital, Guizhou, China.
4
Institute of Translational Medicine, Zhejiang University Hangzhou, Zhejiang, China.
5
Department of Cardiology, Hangzhou First People's Hospital, Hangzhou, China. hjyuo@163.com.
6
Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China. wangjianan111@zju.edu.cn.
7
Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China. wangjianan111@zju.edu.cn.

Abstract

Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.

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