Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion.
Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion.
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DOI：
10.1016/j.bbadis.2014.05.012
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Jie Xu;Xinghua Qin;Xiaoqing Cai;Lu Yang;Yuan Xing;Jun Li;Li-hua Zhang;Ying Tang;
中科院分区：
文献类型：
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作者：
Jie Xu;Xinghua Qin;Xiaoqing Cai;Lu Yang;Yuan Xing;Jun Li;Li-hua Zhang;Ying Tang;
c-Jun N-末端激酶（JNK）是一种应激活化的促分裂原活化蛋白激酶，在疾病条件下启动细胞凋亡中起核心作用。最近的研究表明，线粒体JNK信号通路是缺血性心肌功能障碍的部分原因，但其潜在机制尚不清楚。在这里，我们首次报道了线粒体JNK的激活，而不是JNK在线粒体上的定位，诱导自噬和凋亡，并减轻心肌缺血/再灌注损伤。心肌缺血/再灌注诱导线粒体JNK磷酸化的显着增加，而JNK线粒体定位减少。用Tat-SabKIM 1（一种阻断JNK与线粒体相互作用的反转肽）治疗可降低再灌注后线粒体JNK活化，而不影响JNK线粒体定位。Tat-SabKIM 1处理减少Bcl 2调节的自噬、细胞色素c介导的细胞凋亡和心肌梗死面积。值得注意的是，使用Tat-SabKIM 1选择性抑制线粒体JNK激活产生了与使用JNK抑制剂SP 600125抑制通用JNK激活相似的梗死面积减小效果。此外，胰岛素治疗的动物表现出显着抑制线粒体JNK活化伴随着减少梗死面积和减少自噬和凋亡后再灌注。总之，这些发现表明，线粒体JNK激活，而不是JNK线粒体定位，诱导自噬和凋亡，并加剧心肌缺血/再灌注损伤。胰岛素选择性地抑制线粒体JNK的激活，有助于胰岛素对心肌缺血/再灌注损伤的心脏保护作用。这篇文章是一个特殊问题的一部分，题为：自噬和蛋白质质量控制在心脏代谢疾病。
c-Jun N-terminal kinase (JNK) is a stress-activated mitogen-activated protein kinase that plays a central role in initiating apoptosis in disease conditions. Recent studies have shown that mitochondrial JNK signaling is partly responsible for ischemic myocardial dysfunction; however, the underlying mechanism remains unclear. Here we report for the first time that activation of mitochondrial JNK, rather than JNK localization on mitochondria, induces autophagy and apoptosis and aggravates myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion induced a dominant increase of mitochondrial JNK phosphorylation, while JNK mitochondrial localization was reduced. Treatment with Tat-SabKIM1, a retro-inverso peptide which blocks JNK interaction with mitochondria, decreased mitochondrial JNK activation without affecting JNK mitochondrial localization following reperfusion. Tat-SabKIM1treatment reduced Bcl2-regulated autophagy, cytochrome c-mediated apoptosis and myocardial infarct size. Notably, selective inhibition of mitochondrial JNK activation using Tat-SabKIM1produced a similar infarct size-reducing effect as inhibiting universal JNK activation with JNK inhibitor SP600125. Moreover, insulin-treated animals exhibited significantly dampened mitochondrial JNK activation accompanied by reduced infarct size and diminished autophagy and apoptosis following reperfusion. Taken together, these findings demonstrate that mitochondrial JNK activation, rather than JNK mitochondrial localization, induces autophagy and apoptosis and exacerbates myocardial ischemia/reperfusion injury. Insulin selectively inhibits mitochondrial JNK activation, contributing to insulin cardioprotection against myocardial ischemic/reperfusion injury. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.