Review Article

Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury

Figure 1

The role of RIP-1 in programmed necrosis. Following neonatal HI, members of the TNFR superfamily (also called death receptors, DR) are activated by their ligands (DR-L) (i.e., FasL, TNF-α). In the setting of energy sufficiency and upon TNFR activation, TNFR undergoes a conformational modification of its cytoplasmic portion allowing the interaction with receptor interacting protein (RIP)-1 with the death domain (DD), TNFR-associated death domain (TRADD), and TNFR-associated factor (TRAF)-2 and -5. They in turn recruit the cellular inhibitor of apoptosis (cIAP) forming the complex I. cIAP inhibits caspase-3 activation and allows ubiquitylation of RIP-1. Next, transforming growth factor-β-activated kinase (TAK)-1/TAK-1 binding protein (TAB)-2/TAB-3 form a complex that binds to ubiquitin residues on RIP-1 and activates nuclear factor-κB (NFκB). This may occur via a p38 mitogen-activated-protein-kinase-(p38-MAPK-) dependent pathway. Complex I may interact with NADPH oxidase (NOX 1) producing ROS, also possibly triggering programmed necrosis. Deubiquitylation of RIP-1 by the enzyme cylindromatosis (CYLD) favors the transformation of complex I to complex II binding to the internalized death-inducing-signaling-complex (DISC, formed by FAS-associated protein with death domain (FADD) and procaspase-8 (Pro-C8)) and RIP-3 (Complex II). If energy is only partially insufficient, RIP-1 activates caspase-8 (C8) signaling for classical apoptosis via intrinsic (where truncated BID binds to the outer mitochondrial membrane allowing the release of cytochrome C (Cyt C) and triggering apoptosome formation) or extrinsic pathway resulting in caspase-3 activation. In this setting, caspase-8 cleaves RIP-1 and RIP-3 preserving signal for apoptosis; however, if energy failure evolves, caspase activity declines favoring (i) preservation of the RIP-1 kinase activity, (ii) decrease in RIP-3/FADD constitutive interaction, and (iii) autophosphorylation between RIP-1 with RIP-3 at the RIP homotypic interaction motif (RHIM) forming the necrosome. Necrosome induces reactive oxygen species (ROS) production via activation of NOX 1 at the cellular membrane or direct effects in the mitochondria. ROS cause DNA alkylation increasing activation of calpain-dependent poly(ADP-ribose)polymerase-1 (PARP-1) which is normally required for DNA repair. Hyperactivation of PARP-1 induces ATP depletion and apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus which in turn produces further DNA damage and PARP-1 activation. Necrosome formation is a potential intermediate step that follows PARP-1 activation potential intermediate steps that follow PARP-1 activation. There is some evidence that it produces ATP depletion via inhibition of adenine nucleotide translocase (ANT) in the inner mitochondrial membrane. Mitochondrial dysfunction is likely at the core of the events resulting in programmed necrosis.
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