DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways.
DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways.
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DOI：
10.1016/j.redox.2017.11.004
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Jin Q;Li R;Hu N;Xin T;Zhu P;Hu S;Ma S;Zhu H;Ren J;Zhou H
线粒体分裂和选择性线粒体自噬（mitochondrial autophagy，mitophagy）形成线粒体质量控制的重要轴，在心肌缺血再灌注损伤的发展中起着关键作用。然而，裂变/线粒体自噬的精确上游分子机制仍不清楚。双特异性蛋白磷酸酶1（DUSP 1）调节心脏代谢，但其在再灌注心脏中的生理作用，特别是其对线粒体稳态的影响尚不清楚。在这里，我们证明了心脏DUSP 1在急性心脏IR损伤后下调。在体内，与野生型小鼠相比，DUSP 1转基因小鼠（DUSP 1 TG小鼠）表现出更小的梗死面积和改善的心肌功能。在体外，IR诱导的DUSP 1缺陷促进JNK的激活，从而上调线粒体分裂因子（Mff）的表达。Mff的高表达水平与线粒体分裂和线粒体凋亡的升高相关。此外，DUSP 1的缺失还通过JNK放大了Bnip 3磷酸化激活，导致线粒体自噬的激活。增加的线粒体自噬明显消耗线粒体质量，导致线粒体代谢紊乱。然而，DUSP 1的重新引入钝化了Mff/Bnip 3的激活，因此通过灭活JNK途径减轻了致命的线粒体分裂/线粒体自噬，为IR应激后的心肌组织提供了存活优势。我们的研究结果表明，DUSP 1及其下游JNK通路是通过抑制Mff介导的线粒体分裂和Bnip 3所需的线粒体自噬来保护IR损伤的治疗靶点。IR损伤诱导DUSP 1下调。DUSP 1的缺失导致JNK磷酸化的增加。JNK激活Mff和Bnip 3，分别导致致命的线粒体分裂和线粒体自噬。分裂和线粒体自噬通过触发半胱天冬酶9相关的凋亡和线粒体能量紊乱诱导细胞损伤。
Mitochondrial fission and selective mitochondrial autophagy (mitophagy) form an essential axis of mitochondrial quality control that plays a critical role in the development of cardiac ischemia-reperfusion (IR) injury. However, the precise upstream molecular mechanism of fission/mitophagy remains unclear. Dual-specificity protein phosphatase1 (DUSP1) regulates cardiac metabolism, but its physiological contribution in the reperfused heart, particularly its influence on mitochondrial homeostasis, is unknown. Here, we demonstrated that cardiac DUSP1 was downregulated following acute cardiac IR injury. In vivo, compared to wild-type mice, DUSP1 transgenic mice (DUSP1TG mice) demonstrated a smaller infarcted area and the improved myocardial function. In vitro, the IR-induced DUSP1 deficiency promoted the activation of JNK which upregulated the expression of the mitochondrial fission factor (Mff). A higher expression level of Mff was associated with elevated mitochondrial fission and mitochondrial apoptosis. Additionally, the loss of DUSP1 also amplified the Bnip3 phosphorylated activation via JNK, leading to the activation of mitophagy. Increased mitophagy overtly consumed mitochondrial mass resulting into the mitochondrial metabolism disorder. However, the reintroduction of DUSP1 blunted Mff/Bnip3 activation and therefore alleviated the fatal mitochondrial fission/mitophagy by inactivating the JNK pathway, providing a survival advantage to myocardial tissue following IR stress. The results of our study suggest that DUSP1 and its downstream JNK pathway are therapeutic targets for conferring protection against IR injury by repressing Mff-mediated mitochondrial fission and Bnip3-required mitophagy. IR injury induces DUSP1 downregulation. Loss of DUSP1 leads to an increase in JNK phosphorylation. JNK activates Mff and Bnip3, contributing to the fatal mitochondrial fission and mitophagy, respectively. Fission and mitophagy induces cell damage via trigging caspase9-related apoptosis and mitochondrial energy disorder.
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