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

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 Ml, (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.