Free Radic Biol Med 97:418C26
Free Radic Biol Med 97:418C26. mitochondrial bax translocation and cytochrome c release, mobilization of lysosomal iron and the activation of receptor interacting protein kinases and the inflammasome raised the question whether other emerging modes of cell death like apoptosis, necroptosis, ferroptosis and pyroptosis could also play a role. The current review summarizes the key mechanisms of APAP-induced liver injury and compares these with important features of the newly described modes of cell death. Based on the preponderance of experimental and clinical evidence, the mode of APAP-induced cell death should be termed programmed necrosis; despite some overlap with other modes of cell death, APAP hepatotoxicity does not fulfill the characteristics of either apoptosis, necroptosis, ferroptosis, pyroptosis or autophagic cell death. (Gujral et al., 2002). The more recently recognized intricate signaling pathways involved in the initiation, amplification and propagation of the stress within the cell ultimately leading to cell death also led to the use of the term and (Sharma et al., 2012; Ramachandran et al., 2013; Zhang et al., 2014). These observations led to the characterization of APAP-induced cell death as necroptotic (Zhang et al., 2014). However, necrostatin-1 has off-target effects and is not specific for RIPK1 (Degterev et al., 2013). Nevertheless, gene deletion experiments with RIPK1 have confirmed the potential role of RIPK1 in APAP toxicity (Dara et al., 2015) but the role of RIPK1 in apoptosis and RIPK1-impartial mechanisms of necrosome formation makes RIPK1 not specific for necroptosis. APAP overdose induces RIPK3 in the liver and in hepatocytes and RIPK3 knock-out mice as well as morpholino-based gene knock-down has been shown to be protective during the early phase of APAP-induced liver injury (Ramachandran et al., 2013). These findings with RIPK3 knock-out mice were confirmed by some investigators (Deutsch et al., 2015) but not by others (Dara et Acta2 al., 2015). In addition, an inhibitor of RIPK3 has been shown to protect against APAP-induced cell death in human hepatocytes (Li et al., 2014). We have recently exhibited that scavenging mitochondrial superoxide inhibited APAP-induced RIPK3 expression and caspase activation and apoptotic morphology was obvious in hepatocytes in RIPK3-deficient mice after APAP (Du et al., 2019), suggesting that RIPK3 influenced the mode of cell death after APAP. Nevertheless, the reason for the controversial findings remains unclear (Yang et al., 2016) and a better understanding of the function of RIPK3 in the pathophysiology of APAP is needed. The second crucial mediator of necroptosis, MLKL, is usually expressed in AT 56 the liver and in hepatocytes but deficiency of this gene did not reduce APAP toxicity (Dara et al., 2015). Thus, despite the expression and induction of RIPKs and MLKL during APAP toxicity there is no consistent evidence for the involvement of these genes in APAP-induced cell death and therefore, necroptosis is unlikely to play a critical role. This is also supported by the fact that TNF- is not a critical mediator of APAP-induced cell death (Boess et al., 1998). APOPTOSIS Apoptosis was the first described form of programmed cell death and considerable investigations over the last decades AT 56 revealed many details of the cell death pathway. Based on the initiation, extrinsic and intrinsic pathways are distinguished. During extrinsic apoptosis, ligands, e.g. Fas-ligand or TNF-, react with their receptors, e.g. Fas receptor or TNF receptor 1, around the cell surface and trigger the trimerization of the receptor. Through the death domain of the receptor, pro-caspase-8 is usually bound and activated. Active caspase-8 can either directly cleave and activate effector caspases such as caspase-3 (type I cell) or cleave bid (type II cell), which then translocates to the mitochondria and together with other Bcl-2 family members (bax, bak, bad) permeabilizes the outer mitochondrial membrane and releases cytochrome c and Smac/Diablo. Cytochrome c together with ATP and procaspase-9 binds to apoptotic protease activating factor-1 (APAF-1) inducing the activation of caspase-9, which then activates caspase-3 (Physique 1). Smac/Diablo inhibits the cytosolic inhibitors of apoptosis proteins (IAPs), which prevent inactivation of caspases by IAPs. The intrinsic AT 56 pathway of apoptosis starts with inducing bax translation to the mitochondria or other signals that trigger the release of pro-apoptotic mediators from mitochondria, which induces the caspase cascade by activation of caspase-9. In either case, the effector caspases degrade a variety of intracellular macromolecules triggering shrinkage and fragmentation of the cell into apoptotic body. In addition, there is chromatin condensation and DNA fragmentation induced by the caspase-activated DNase (CAD). This enzyme is usually kept inactive in the cytosol by an inhibitor (ICAD), which.