FUNDC1-dependent mitophagy induced by tPA protects neurons against cerebral ischemia-reperfusion injury.
FUNDC1-dependent mitophagy induced by tPA protects neurons against cerebral ischemia-reperfusion injury.
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由TPA诱导的基金C1依赖性线索可保护神经元免受脑缺血再灌注损伤。
DOI：
10.1016/j.redox.2020.101792
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Cai Y;Yang E;Yao X;Zhang X;Wang Q;Wang Y;Liu J;Fan W;Yi K;Kang C;Wu J
线粒体自噬（mitophagy）在脑缺血再灌注损伤中起重要作用，但其机制尚不清楚。组织型纤溶酶原激活剂（tPA）是临床治疗缺血性脑卒中最重要的溶栓药物，具有神经保护作用。在这里，我们探讨了tPA对IR后神经细胞凋亡和线粒体自噬的影响。我们发现，敲除tPA基因显著加重脑损伤，增加神经细胞凋亡和线粒体损伤。神经元暴露于tPA降低损伤严重程度并保护线粒体。进一步的研究表明，tPA的这种保护作用是通过调节FUNDC 1介导的线粒体自噬来实现的。此外，我们发现tPA通过激活AMPK的磷酸化来增强FUNDC 1的表达水平。总之，我们的研究结果证实，tPA发挥神经保护作用，通过增加AMPK的磷酸化和FUNDC 1的表达，从而抑制细胞凋亡和改善线粒体功能。脑缺血后，神经元释放的tPA具有神经保护作用。tPA调节线粒体自噬以降低氧化应激并抑制细胞凋亡。线粒体膜蛋白FUNDC 1和AMPK信号通路参与tPA的神经保护过程。
Autophagy of mitochondria, termed mitophagy, plays an important role in cerebral ischemia-reperfusion (IR) injury, but the mechanism is not yet clear. Tissue-type plasminogen activator (tPA) is the most important thrombolytic drug in the clinical treatment of ischemic stroke and has neuroprotective effects. Here, we explored the effects of tPA on neuronal apoptosis and mitophagy following IR. We found that knocking out the tPA gene significantly aggravated brain injury and increased neuronal apoptosis and mitochondrial damage. Exposure of neurons to tPA reduced injury severity and protected mitochondria. Further studies demonstrated that this protective effect of tPA was achieved via regulation of FUNDC1-mediated mitophagy. Furthermore, we found that tPA enhanced the expression level of FUNDC1 by activating the phosphorylation of AMPK. In summary, our results confirm that tPA exerts neuroprotective effects by increasing the phosphorylation of AMPK and the expression of FUNDC1, thereby inhibiting apoptosis and improving mitochondrial function. After cerebral ischemia, tPA released by neurons has a neuroprotective effect. tPA modulates mitophagy to decrease oxidative stress and inhibit apoptosis. The mitochondrial membrane protein FUNDC1 and the AMPK signaling pathway are involved in the neuroprotective process of tPA.
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影响因子：
8.3
作者：
Baek SH;Noh AR;Kim KA;Akram M;Shin YJ;Kim ES;Yu SW;Majid A;Bae ON
通讯作者：
Bae ON
影响因子：
37.8
作者：
Wu, Shengnan;Lu, Qiulun;Zou, Ming-Hui
通讯作者：
Zou, Ming-Hui
影响因子：
6.1
作者：
Jeanneret V;Yepes M
通讯作者：
Yepes M
影响因子：
6.3
作者：
Haile, Woldeab B.;Wu, Jialing;Yepes, Manuel
通讯作者：
Yepes, Manuel
DOI：
10.1016/j.bbrc.2014.01.032
发表时间：
2014-02-07
影响因子：
3.1
作者：
Li, Qiang;Zhang, Ting;Sun, Xiaojiang
通讯作者：
Sun, Xiaojiang