Chang Wei, Feng Min, Li Yuexia, Sun Ya, Sun Lulu
Department of Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
J Cell Physiol. 2019 Sep;234(9):16148-16159. doi: 10.1002/jcp.28273. Epub 2019 Feb 10.
Mitochondrial stress has been acknowledged as the pathogenesis for tumor necrosis factor-α (TNF-α)-induced septic cardiomyopathy. Recently, MAP kinase phosphatase 1 (MKP1) downregulation and mitochondrial fragmentation modulate the mitochondrial stress via multiple molecular mechanisms. Thereby, the goal of our current work is to figure out the functional role of mitochondrial fragmentation in TNF-α-induced septic cardiomyopathy. Our results exhibited that MKP1 expression was significantly repressed in hearts treated by TNF-α. Overexpression of MKP1 sustained cardiac function and attenuated cardiomyocytes death in TNF-α-treated hearts. At the molecular levels, decreased MKP1 induced mitochondrial stress, as indicated by mitochondrial calcium overloading, mitochondrial oxidative stress, mitochondrial antioxidant downregulation, mitochondrial membrane potential reduction, mitochondrial bioenergetics suppression, mitochondrial proapoptotic factors liberation, and caspase-9 apoptotic pathway activation. To the end, we illustrated that MKP1-modulated mitochondrial stress via mitochondrial fragmentation; reactivation of mitochondrial fragmentation abolished the protective effect of MKP1 overexpression on mitochondrial function. Further, MKP1 affected mitochondrial division in a mechanism through the JNK-MIEF1 axis. Blockade of JNK pathway abolished the regulatory actions of MKP1 on mitochondrial division. Altogether, our results identify MKP1 as a novel cardioprotective factor in TNF-α-related septic cardiomyopathy via affecting mitochondrial division by the way of JNK-MIEF1 signaling pathway. Therefore, MKP1 expression, mitochondrial fragmentation modification, and JNK-MIEF1 pathway modulation may be considered as potential therapeutic targets for the treatment of cardiac injury induced by sepsis.
线粒体应激已被公认为肿瘤坏死因子-α（TNF-α）诱导的脓毒症性心肌病的发病机制。最近，丝裂原活化蛋白激酶磷酸酶1（MKP1）的下调和线粒体碎片化通过多种分子机制调节线粒体应激。因此，我们当前工作的目标是弄清楚线粒体碎片化在TNF-α诱导的脓毒症性心肌病中的功能作用。我们的结果显示，在TNF-α处理的心脏中，MKP1表达显著受到抑制。MKP1的过表达维持了心脏功能，并减轻了TNF-α处理的心脏中的心肌细胞死亡。在分子水平上，MKP1的减少诱导了线粒体应激，表现为线粒体钙超载、线粒体氧化应激、线粒体抗氧化剂下调、线粒体膜电位降低、线粒体生物能量学抑制、线粒体促凋亡因子释放以及半胱天冬酶-9凋亡途径激活。最后，我们阐明了MKP1通过线粒体碎片化调节线粒体应激；线粒体碎片化的重新激活消除了MKP1过表达对线粒体功能的保护作用。此外，MKP1通过JNK-MIEF1轴机制影响线粒体分裂。JNK途径的阻断消除了MKP1对线粒体分裂的调节作用。总之，我们的结果确定MKP1是TNF-α相关脓毒症性心肌病中的一种新型心脏保护因子，它通过JNK-MIEF1信号通路影响线粒体分裂。因此，MKP1表达、线粒体碎片化修饰和JNK-MIEF1途径调节可被视为治疗脓毒症诱导的心脏损伤的潜在治疗靶点。
