Regulated Necrosis

Stable Identifier
R-HSA-5218859
Type
Pathway
Species
Homo sapiens
Synonyms
Programmed necrosis
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Necrosis has traditionally been considered as a passive, unregulated cell death. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by genetically controlled and highly regulated cellular process that is morphologically characterized by a loss of cell membrane integrity, intracellular organelles and/or the entire cell swelling (oncosis) (Rello S et al. 2005; Galluzzi L et al. 2007; Berghe TV et al. 2014). The morphological hallmarks of the nectotic death have been associated with different forms of programmed cell death including (but not limited to) parthanatos, necroptosis, glutamate-induced oxytosis, ferroptosis, inflammasome-mediated necrosis etc. Each of them can be triggered under certain pathophysiological conditions. For example UV, ROS or alkylating agents may induce poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation (parthanatos), while tumor necrosis factor (TNF) or toll like receptor ligands (LPS and dsRNA) can trigger necrosome-mediated necroptosis. The initiation events, e.g., PARP1 hyperactivation, necrosome formation, activation of NADPH oxidases, in turn trigger one or several common intracellular signals such as NAD+ and ATP-depletion, enhanced Ca2+ influx, dysregulation of the redox status, increased production of reactive oxygen species (ROS) and the activity of phospholipases. These signals affect cellular organelles and membranes leading to osmotic swelling, massive energy depletion, lipid peroxidation and the loss of lysosomal membrane integrity. Regulated or programmed necrosis eventually leads to cell lysis and release of cytoplasmic content into the extracellular region that is often associated with a tissue damage resulting in an intense inflammatory response.

The Reactome module describes necroptosis as the most characterized form of regulated necrosis. The molecular mechanisms behind the other types of regulated necrosis as well as interconnectivity among them need further studies.

Literature References
PubMed ID Title Journal Year
24563506 True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity

Mocarski, ES, Kaiser, WJ, Livingston-Rosanoff, D, Upton, JW, Daley-Bauer, LP

J. Immunol. 2014
24452471 Regulated necrosis: the expanding network of non-apoptotic cell death pathways

Vanden Berghe, T, Linkermann, A, Jouan-Lanhouet, S, Walczak, H, Vandenabeele, P

Nat. Rev. Mol. Cell Biol. 2014
23770045 Crosstalk between apoptosis, necrosis and autophagy

Nikoletopoulou, V, Markaki, M, Palikaras, K, Tavernarakis, N

Biochim. Biophys. Acta 2013
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