Activation of UQCRC2-dependent mitophagy by tetramethylpyrazine inhibits MLKL-mediated hepatocyte necroptosis in alcoholic liver disease
Activation of UQCRC2-dependent mitophagy by tetramethylpyrazine inhibits MLKL-mediated hepatocyte necroptosis in alcoholic liver disease
复制标题
四甲基吡嗪激活 UQCRC2 依赖性线粒体自噬抑制酒精性肝病中 MLKL 介导的肝细胞坏死性凋亡
DOI：
10.1016/j.freeradbiomed.2021.11.008
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发表时间：
2021
影响因子：
7.4
通讯作者：
Chunfeng Lu
中科院分区：
文献类型：
--
作者：
Ying Zhou;Ruoman Wu;Xinqi Wang;Yiming Jiang;Wenxuan Xu;Yunyun Shao;Chunxiao Yue;Wenqian Shi;Huanhuan Jin;Ting Ge;Xiaofeng Bao;Chunfeng Lu
肝细胞坏死是酒精性肝病的核心病理事件。本研究旨在探讨从黄芪中提取的保肝活性成分川芎嗪（TMP）对酒精诱导的肝细胞坏死的抑制作用，并进一步阐明其分子机制。结果显示，TMP减少了乙醇暴露肝细胞中受体相互作用蛋白激酶1（RIPK1）/RIPK3坏死体的激活和混合谱系激酶结构域样蛋白（MLKL）的磷酸化，从而减少了坏死性凋亡和损伤相关分子模式的泄漏。TMP抑制p-MLKL的线粒体转位有助于乙醇损伤肝细胞线粒体功能的恢复。TMP还通过中断p-MLKL和RIPK1/RIPK3坏死体之间的线粒体活性氧（ROS）依赖性正反馈来破坏坏死性凋亡信号回路。此外，TMP通过恢复PINK1/parkin介导的线粒体自噬，促进乙醇孵育肝细胞中受损线粒体的清除。UQCRC2在乙醇暴露的肝细胞中表达下调，TMP处理后UQCRC2表达恢复，抑制TMP降低乙醇暴露的肝细胞线粒体ROS积累、减轻线粒体损伤和增强PINK1/parkin介导的线粒体自噬的能力。类似地，系统性UQCRC 2敲低中断TMP触发自噬信号、抑制坏死性凋亡信号并保护免受酒精性肝损伤、炎症和ROS过度产生的作用。总之，这项工作得出结论，TMP挽救了乙醇攻击肝细胞中的UQCRC 2表达，这有助于通过促进PINK 1/parkin介导的线粒体自噬来抑制坏死性凋亡。这些发现揭示了TMP保肝作用的潜在分子药理学机制，并表明TMP是一种有前途的酒精性肝病治疗候选药物。
Hepatocyte necroptosis is a core pathogenetic event during alcoholic liver disease. This study was aimed to explore the potential of tetramethylpyrazine (TMP), an active hepatoprotective ingredient extracted from Ligusticum Wallichii Franch, in limiting alcohol-triggered hepatocyte necroptosis and further specify the molecular mechanism. Results revealed that TMP reduced activation of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 necrosome in ethanol-exposed hepatocytes and phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which thereby diminished necroptosis and leakage of damage-associated molecular patterns. Suppression on mitochondrial translocation of p-MLKL by TMP contributed to recovery of mitochondrial function in ethanol-damaged hepatocytes. TMP also disrupted necroptotic signal loop by interrupting mitochondrial reactive oxygen species (ROS)-dependent positive feedback between p-MLKL and RIPK1/RIPK3 necrosome. Further, TMP promoted clearance of impaired mitochondria in ethanol-incubated hepatocytes via restoring PINK1/parkin-mediated mitophagy. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) was downregulated in ethanol-exposed hepatocytes, which was restored after TMP treatment.In vitroUQCRC2 knockdown lowered the capacities of TMP in reducing mitochondrial ROS accumulation, relieving mitochondria damage, and enhancing PINK1/parkin-mediated mitophagy in ethanol-exposed hepatocytes. Analogously, systematic UQCRC2 knockdown interrupted the actions of TMP to trigger autophagic signal, repress necroptotic signal, and protect against alcoholic liver injury, inflammation, and ROS overproduction. In conclusion, this work concluded that TMP rescued UQCRC2 expression in ethanol-challenged hepatocytes, which contributed to necroptosis inhibition by facilitating PINK1/parkin-mediated mitophagy. These findings uncovered a potential molecular pharmacological mechanism underlying the hepatoprotective action of TMP and suggested TMP as a promising therapeutic candidate for alcoholic liver disease.