Apoptosis: regulated mechanism of cell death that serves toeliminate unwanted and irreparably damaged cells, with theleast possible host reaction, characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and byrapid recognition and removal of dead cells by phagocytes
Apoptosis is initiated by two major pathways:
Mitochondrial (intrinsic) pathway is triggered by loss ofsurvival signals, DNA damage, and accumulation ofmisfolded proteins (ER stress); associated with leakage ofproapoptotic proteins from mitochondrial membrane intothe cytoplasm, where they trigger caspase activation; inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growthfactors.
Death receptor (extrinsic) pathway is responsible forelimination of self-reactive lymphocytes and damage byCTLs; is initiated by engagement of death receptors(members of the TNF receptor family) by ligands onadjacent cells.
Two other unusual pathways of cell death are necroptosis(which, as the name implies, includes features of both necrosisand apoptosis and is regulated by particular signaling pathways)and pyroptosis, which can lead to the release of proinflammatory cytokines and may initiate apoptosis.
Autophagy is an adaptation to nutrient deprivation in whichcells digest their own organelles and recycle them to provideenergy and substrates. If the stress is too severe for theprocess to cope with it, it results in cell death by apoptosis.
Before discussing individual mechanisms of cell injury and death, some general principles should be emphasized.
The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, low doses of toxins or a brief period of ischemia may lead to reversible cell injury, whereas larger toxin doses or longer ischemic times may result in irreversible injury and cell death.