Abstract
Once thought to be a random process of cell death, necrosis can proceed via a defined molecular mechanism and is integral to physiological and pathological states. In particular a form of necrosis called necroptosis has been the subject of intense investigation. Necroptosis is initiated by tumor necrosis factor-α (TNFα), which leads to the activation of the kinase receptor-interacting protein 1 (RIP1). RIP1 then binds with and activates RIP3 to form the necrosome. RIP3 in turn interacts with and activates the pseudokinase mixed lineage kinase domain-like (MLKL). This complex has then been proposed to induce necrotic death via the induction of mitochondrial dysfunction, with a variety of mechanisms being put forth including: production of mitochondrial reactive oxygen species (ROS), activation of the mitochondrial phosphatase PGAM5, or induction of mitochondrial permeability transition (MPT). However, recent evidence suggests that none of these are involved in necroptosis, and that mitochondria may in fact be dispensable for this process. Therefore, the purpose of this perspective is to discuss the current understanding of necroptosis, and more specifically, what role if any do mitochondria play in this mechanism of cell death.
Highlights
Cells die for a variety of reasons and under myriad circumstances
Zhang et al (2009) found that RIP3 could translocate to the mitochondria where it interacted with the mitochondrial protein glutamate dehydrogenase 1 (GLUD1)
These recent studies would indicate that the execution of programmed necrosis proceeds by a novel, yet to be characterized mitochondrially independent mechanism
Summary
Cells die for a variety of reasons and under myriad circumstances. Cells are thought to undergo three major forms of regulated cell death: apoptosis, autophagy, and necrosis. The most studied and defined molecular necrotic pathway is traditionally mediated by signaling by the tumor necrosis factor-α (TNFα) receptor (TNFR) through RIPs 1 and 3 and subsequently the pseudokinase MLKL and is termed necroptosis (Christofferson et al, 2014; Galluzzi et al, 2014; Vanden Berghe et al, 2014). Variety of guises have been proposed to be mediators of necroptosis, recent data has suggested that they may not be necessary for the execution of the necroptotic program This perspective will summarize the current understanding of necroptosis signaling and discuss whether mitochondria have any role to play in this form of programmed necrosis. In response to TNFα stimulation, TNFR recruits proteins to the plasma membrane (Van Herreweghe et al, 2010; Christofferson et al, 2014; Vanden Berghe et al, 2014). This cytosolic collection of proteins is known as complex IIa and in place of TNFR from complex I contains caspase 8 and adaptor protein FADD
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