Abstract
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.
Highlights
Liver diseases, including hepatitis B, hepatitis C, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and related hepatic fibrosis, liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC), are the leading causes of illness and death worldwide [1]
The results suggest that phosphoglycerate mutase family member 5 (PGAM5) is downstream of receptor-interactive protein kinases 1 (RIPK1)/receptorinteractive protein kinases 3 (RIPK3), induces necroptosis, and protects cells from necroptosis via promoting mitophagy [59] (Figure 1)
Qian et al reported that the RIPK1/RIPK3/mixed lineage kinase domain-like protein (MLKL) signaling pathway was activated in mice with acute liver injury induced by Listeria monocytogenes infection, subsequently leading to necroptosis and hepatic damage
Summary
Liver diseases, including hepatitis B, hepatitis C, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and related hepatic fibrosis, liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC), are the leading causes of illness and death worldwide [1]. Mitochondria play a pivotal role in the generation of cellular energy and biosyn-thesis. They are key in the regulation of various types of cell death, including necroptosis [5,6,7,8], apoptosis [9,10,11], ferroptosis [12,13,14,15], pyroptosis [16], and other forms. We focus on the role of mitochondria-mediated cell necroptosis in acute liver injury, chronic liver hepatitis, liver cirrhosis, and hepatocellular carcinoma, as well as the possible translations of these processes into clinical applications
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