Meta-Biol

• Pathways

A regulated balance between cell survival and cell death is essential for normal development and homeostasis of multicellular organisms. Defects in control of this balance may contribute to autoimmune disease, neurodegeneration, ischemia/reperfusion injury, non alcoholic steatohepatitis (NASH) and cancer.

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; Ros U et al. 2020). 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. Different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. 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 and pyroptosis.

Cell death is a fundamental cellular response that has a crucial role in shaping our bodies during development and in regulating tissue homeostasis by eliminating unwanted cells. There are a number of different forms of cell death, each with a corresponding number of complex subprocesses. The first form of regulated or programmed cell death to be characterized was apoptosis. Evidence has emerged for a number of regulated non-apoptotic cell death pathways, including some with morphological features that were previously attributed to necrosis. More recently necrosis has been subdivided into parts including programmed necrotic cell death processes, such as RIP1-mediated regulated necrosis or pyroptosis.
Reactome currently represents programmed cell death using the model of extrinsic signalling that leads to a molecular decision point pivoting on caspase-8 activation or inhibition. Caspase-8 activation tilts the cell towards apoptosis, while caspase-8 inhibition tilts the cell towards Regulated Necrosis.

The terminology and molecular definitions of cell death-related events annotated here are consistent with the 2015 recommendations of the Nomenclature Committee on Cell Death (NCCD) (Galluzzi L et al. 2015).