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Necrosis & Necroptosis
NECROSIS
Necrosis is the premature death of cells in living tissue and can be caused by external factors to the cell or tissue, such as infection, toxins, cancer, infarction, poisons, ROS (Reactive Oxygen Species), inflammation or trauma.
Historically, cell death has been subdivided into regulated (apoptosis, aka programmed cell death) and unregulated (necrosis) forms. While apoptosis has always been recognized to be a pathway of highly coordinated signaling events which is a naturally occurring cause of cellular death and can often provide beneficial effects to the organism.
Necrosis is morphologically characterized by a gain in cell volume (oncosis), swelling of organelles, plasma membrane rupture and subsequent loss of intracellular contents.
Necrosis or necrotic cell death is almost always detrimental and can be fatal. Currently, necrotic pathways are poorly defined and are still largely identified in negative terms by the absence of apoptotic or autophagic markers.
Biochemically it is characterized by loss of regulation in ion homeostasis, random digestion of DNA & ultimately postlytic of DNA fragmentation. Physiologically, necrosis affects groups of contiguous cells, phagocytosis by macrophages and significant inflammatory immune response.
NECROPTOSIS
Newly research is determining that necrosis is not just a series of unregulated, uncontrollable processes but is in fact a series of 'programmed necrosis' aptly named necroptosis.
Historically, Necrosis has been considered an accidental cell death and not set to determined pathways or cellular regulation. Necrotic cell death is defined by an increase in cell volume, swelling of organelles, plasma membrane rupture and eventual leakage of intracellular components.
Now it is becoming increasingly realized, Neurotic cell death may be executed through defined mechanisms or pathways aptly termed "Necroptosis" (Degterev et al 2005).
In fact, it may be executed via stimulation of tumor necrosis factor alpha (TNFα), FasL and TRAIL. These are the same ligands that activate APOPTOSIS.
Thus, cell death induced by the activation of the death receptor may be accomplished through alternative death pathways or necroptosis. Receptor interacting protein (RIP) kinases constitute a family of seven members, all of which contain a kinase domain (KD). They are crucial regulators of cell survival and death. Specifically, RIP1 kinase activation is required as an upstream regulator of necroptotic death pathway.
Additionally, after TNFα stimulation identified Cylindromatosis (CYLD), a tumor suppressor, as an important regulator for mediating both Apoptosis & Necroptosis. It appears ubiquitination/deubiquination may be involved in the signal transduction of both Apoptosis & Necroptosis.
Preliminary research demonstrates the inhibition of CYLS results in the suppression of Necroptosis by up-regulating wnt signaling. The wnt signaling pathway is a network of proteins best known for their roles in embryogenesis, cancer, basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division.
Necroptosis downstream mechanisms are still very preliminary and require further elucidation. Reactive oxygen species (ROS) is shown to be the executioner of necroptosis from some cell types and research has determined antioxidant treatment does not rescue all cell types from necroptosis.
Mitochondrion are well defined in apoptotic cell death although there is preliminary mitochondrial involvement in necroptosis. Specifically, there is a downstream role for RIP1, adenine nucleotide translocase (ANT) and cyclophilin D (cypD) in the mitochondrial permeability transition has been proposed for necroptosis. In a cardiac ischemia experiment, a reduction in necrotic cell death occurred in cypD-deficient mice (Nakagawa et al. 2005).
Finally, autophagic vesicles are frequently observed in necroptotic cells thus the possibility of autophagy as an execution mechanism for necroptosis. It appear initial thoughts of autophagic cell death could actually be enlighten to demonstrate it is actually necroptosis.
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