State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Department of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Int J Mol Sci. 2020 Dec 23;22(1):66. doi: 10.3390/ijms22010066.
Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease. Necroptosis is a common form of programmed cell death in the liver. Necroptosis can be activated by ligands of death receptors, which then interact with receptor-interactive protein kinases 1 (RIPK1). RIPK1 mediates receptor interacting receptor-interactive protein kinases 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) and necrosome formation. Regarding the molecular mechanisms of mitochondrial-mediated necroptosis, the RIPK1/RIPK3/MLKL necrosome complex can enhance oxidative respiration and generate reactive oxygen species, which can be a crucial factor in the susceptibility of cells to necroptosis. The necrosome complex is also linked to mitochondrial components such as phosphoglycerate mutase family member 5 (PGAM5), metabolic enzymes in the mitochondrial matrix, mitochondrial permeability protein, and cyclophilin D. In this review, we focus on the role of mitochondria-mediated cell necroptosis in acute liver injury, chronic liver diseases, and hepatocellular carcinoma, and its possible translation into clinical applications.
细胞死亡代表了一种基本的生物学范例，几乎影响着每一种肝脏疾病的结局和长期后果。细胞程序性坏死是肝脏中常见的一种细胞死亡形式。细胞程序性坏死可以通过死亡受体的配体激活，然后与受体相互作用蛋白激酶 1（RIPK1）相互作用。RIPK1 介导受体相互作用蛋白激酶 3（RIPK3）和混合谱系激酶结构域样蛋白（MLKL）以及坏死小体的形成。关于线粒体介导的细胞程序性坏死的分子机制，RIPK1/RIPK3/MLKL 坏死小体复合物可以增强氧化呼吸并产生活性氧，这可能是细胞对细胞程序性坏死易感性的关键因素。坏死小体复合物还与线粒体成分如磷酸甘油酸变位酶家族成员 5（PGAM5）、线粒体基质中的代谢酶、线粒体通透性蛋白和亲环素 D 相关。在这篇综述中，我们重点讨论了线粒体介导的细胞程序性坏死在急性肝损伤、慢性肝病和肝细胞癌中的作用及其可能转化为临床应用。
