Apoptosis
Apoptosis, also known as programmed cell death, is a highly regulated cellular suicide process that can be triggered by various extracellular or intracellular death signals. It involves a complex network of signaling pathways that orchestrate controlled cell shrinkage, membrane blebbing and nuclear fragmentation. Various apoptosis signaling pathways are involved in this tightly regulated process.
Apoptosis
Cell death can occur through three different yet overlapping mechanisms: apoptosis, autophagy and necrosis. (1) Apoptosis, also known as programmed cell death, was first described in 1972. (2) The process results in controlled cell shrinkage and nuclear fragmentation via the action of proteolytic enzymes called caspases, as well as an anti-inflammatory cytokine release. In contrast, necrosis signals via receptor-interacting serine/threonine-protein kinase 1 (RIPK1 or RIP1), leading to cell swelling, lysis and a pro-inflammatory cytokine release. (3) Autophagy destroys the cell's damaged proteins and organelles via an intracellular catabolic process in the lysosome. (4)
Multiple physiological processes require the removal of specific cells by a controlled cell-death program. For example, tissue remodeling activates apoptosis, whereas energy metabolism and growth regulation responses rely on autophagy. Developmental processes often activate apoptosis, while bodily injuries or infection more commonly induce necrosis.
The molecular mechanisms behind these cell death pathways overlap and can be co-activated by similar upstream stimuli. For example, apoptosis and necrosis both signal through the death domain receptors FAS, TNFRSF1A (TNFR1) and TNFRSF10A (TRAIL-R), (5) while autophagy and apoptosis share BCL2 family members as key regulators. (6)
Apoptosis is a highly regulated process that includes two main pathways: intrinsic and extrinsic. The intrinsic apoptosis pathway, which is also known as mitochondrial-mediated apoptosis, is activated by signals from within cell in response to stress such as DNA damage or radiation, which change the inner mitochondrial membrane potential and result in the release of pro-apoptotic proteins into the cytosol. (7) These proteins activate caspase 9 and caspase 3.
The extrinsic apoptosis pathway is triggered in response to signals from other cells, such as the ligation of tumor necrosis factor (TNF) family death receptors. (7) The TNF receptors in turn recruit and activate caspase 8, leading to the activation of caspases 3, 6 and 7 and subsequent apoptotic steps.
Abnormalities in apoptosis have been associated with human disease. (5) For example, disruptions that prevent cellular apoptosis allow cells to live longer than they should, increasing the possibility of developing cancer, inflammatory disease or viral infection. Conversely, overactive apoptosis results in the death of cells that are not actually supposed to die and can lead to the development of neurodegenerative diseases such as such as Alzheimer's and Parkinson's, hematologic disorders such as the loss of CD4+ lymphocytes in HIV positive patients (8), and tissue damage.
References
1. D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int. 2019 Jun;43(6):582-592. doi: 10.1002/cbin.11137.
2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239-57. doi: 10.1038/bjc.1972.33.
3. Moriwaki K, Chan FK. Necrosis-dependent and independent signaling of the RIP kinases in inflammation. Cytokine Growth Factor Rev. 2014 Apr;25(2):167-74. doi: 10.1016/j.cytogfr.2013.12.013.
4. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008 Feb 28;451(7182):1069-75. doi: 10.1038/nature06639.
5. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007 Jun;35(4):495-516. doi: 10.1080/01926230701320337.
6. Heath-Engel HM, Chang NC, Shore GC. The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene. 2008 Oct 27;27(50):6419-33. doi: 10.1038/onc.2008.309.
7. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002 Apr;2(4):277-88. doi: 10.1038/nrc776.
8. Jabea Ekabe C, Asaba Clinton N, Agyei EK, Kehbila J. Role of Apoptosis in HIV Pathogenesis. Adv Virol. 2022 Apr 14;2022:8148119. doi: 10.1155/2022/8148119.