Leptin enhances glycolysis via OPA1-mediated mitochondrial fusion to promote mesenchymal stem cell survival
Leptin enhances glycolysis via OPA1-mediated mitochondrial fusion to promote mesenchymal stem cell survival
复制标题
DOI：
10.3892/ijmm.2019.4189
复制
发表时间：
2019-07-01
影响因子：
5.4
通讯作者：
Yang, Long
中科院分区：
文献类型：
--
作者：
Yang, Fan;Li, Bing;Yang, Long
间充质干细胞(MSCs)移植是治疗心血管疾病的一种潜在方法。然而，移植的MSCs存活率低是提高其临床疗效的主要障碍。越来越多的证据表明，低氧预适应(HPC)可以提高MSCs的存活率。已有研究报道，瘦素通过增加视神经萎缩1(OPA1)依赖的线粒体融合，在HPC增强MSC存活的过程中发挥关键作用。骨髓间充质干细胞的存活主要依靠糖酵解作为能量来源。瘦素与血糖动态平衡的密切关系引起了科学界的浓厚兴趣。此外，新出现的证据表明，线粒体动力学(融合和分裂)与糖酵解的改变有关。本研究的目的是探讨瘦素是否通过代谢调节增加MSC的存活率。瘦素调节的OPA1表达增加与糖酵解增加有关。然而，在使用选择性siRNA沉默OPA1后，瘦素的糖酵解作用被取消，这表明OPA1直接调节糖酵解。此外，瘦素对钠-葡萄糖同向转运体1(SGLT1)的激活有明显的诱导作用。然而，瘦素诱导的糖酵解主要被SGLT1抑制剂治疗所阻断。因此，瘦素主要通过激活SGLT1来调节OPA1依赖的糖酵解以提高MSC的存活率。因此，我们确定了线粒体动态介导糖酵解的关键信号通路Leptin/OPA1/SGLT1，这可能优化MSCs的治疗效率。
Transplantation of mesenchymal stem cells (MSCs) is emerging as a potential therapy for cardiovascular diseases. However, the poor survival of transplanted MSCs is a major obstacle to improving their clinical efficacy. Accumulating evidence indicates that hypoxic preconditioning (HPC) can improve the survival of MSCs. It has been previously reported that leptin plays a critical role in HPC-enhanced MSC survival through increasing optic atrophy 1 (OPA1)-dependent mitochondrial fusion. Survival of MSCs mainly relies on glycolysis as an energy source. The close relationship between leptin and glucose homeostasis has attracted intense scientific interest. Furthermore, emerging evidence indicates that mitochondrial dynamics (fusion and fission) are associated with alterations in glycolysis. The aim of the present study was to investigate whether leptin increases MSC survival through metabolic regulation. Leptin-modulated increased OPA1 expression was found to be associated with increased glycolysis. However, the glycolytic efficacy of leptin was abrogated after silencing OPA1 using a selective siRNA, suggesting that OPA1 directly regulates glycolysis. Furthermore, the activation of sodium-glucose symporter 1 (SGLT1) was markedly induced by leptin. However, leptin-induced glycolysis was primarily blocked by SGLT1 inhibitor treatment. Thus, leptin regulates OPA1-dependent glycolysis to improve MSC survival primarily through SGLT1 activation. We therefore identified a pivotal leptin/OPA1/SGLT1 signaling pathway for mitochondrial dynamic-mediated glycolysis, which may optimize the therapeutic efficiency of MSCs.