Editing Programmed cell death (section)

==Types==
[[Image:Signal transduction pathways.svg|thumb|right|Overview of signal transduction pathways involved in [[apoptosis]]]]
* [[Apoptosis]] or Type I cell-death.
* [[Autophagic cell death]] or Type II cell-death. (''[[Cytoplasm]]ic'': characterized by the formation of large [[vacuoles]] that eat away [[organelles]] in a specific sequence prior to the destruction of the [[cell nucleus|nucleus]].)<ref>
{{cite journal
 |vauthors=Schwartz LM, Smith SW, Jones ME, Osborne BA |year = 1993
 |title = Do all programmed cell deaths occur via apoptosis?
 |journal = [[PNAS]]
 |volume = 90 |issue = 3 |pages = 980–4
 |pmid = 8430112
 |pmc = 45794
 |doi = 10.1073/pnas.90.3.980
|bibcode = 1993PNAS...90..980S
 |doi-access = free
 }};and, for a more recent view, see {{cite journal
 |doi = 10.1111/j.1749-6632.2000.tb05594.x
 |vauthors=Bursch W, Ellinger A, Gerner C, Fröhwein U, Schulte-Hermann R |year = 2000
 |title = Programmed cell death (PCD). Apoptosis, autophagic PCD, or others?
 |journal = [[Annals of the New York Academy of Sciences]]
 |volume = 926 | issue = 1| pages = 1–12
 |pmid = 11193023
|bibcode=2000NYASA.926....1B |s2cid=27315958 }}</ref>

=== Apoptosis ===

[[Apoptosis]] is the process of programmed cell death (PCD) that may occur in [[multicellular organisms]].<ref>{{cite book|last=Green|first=Douglas|title=Means To An End|year=2011|publisher=Cold Spring Harbor Laboratory Press|location=New York|isbn=978-0-87969-888-1 |url=http://celldeathbook.wordpress.com/}}</ref> [[Biochemical]] events lead to characteristic cell changes ([[Morphology (biology)|morphology]]) and death. These changes include [[Bleb (cell biology)|blebbing]], cell shrinkage, [[Cell nucleus|nuclear]] fragmentation, [[chromatin condensation]], and [[chromosome|chromosomal]] [[DNA]] fragmentation. It is now thought that- in a developmental context- cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.<ref name="Apoptosis or programmed cell death?">{{cite journal|last=D. Bowen|first=Ivor|title=Cell Biology International 17|journal=Cell Biology International|volume=17|issue=4|year=1993|pages=365–380|url=http://www.cellbiolint.org/cbi/017/cbi0170365.htm#CitedBy|access-date=2012-10-03|archive-url=https://web.archive.org/web/20140312224446/http://www.cellbiolint.org/cbi/017/cbi0170365.htm#CitedBy|archive-date=2014-03-12|url-status=dead|doi=10.1006/cbir.1993.1075|pmid=8318948|s2cid=31016389|url-access=subscription}}</ref>

==== Extrinsic Vs. Intrinsic Pathways ====
There are two different potential pathways that may be followed when apoptosis is needed. There is the extrinsic pathway and the intrinsic pathway. Both pathways involve the use of caspases - crucial to cell death.{{cn|date=November 2024}}

===== Extrinsic Pathway =====
{{See also|Activation-induced cell death}}
The extrinsic pathway involves specific receptor ligand interaction. Either the FAS ligand binds to the FAS receptor or the TNF-alpha ligand can bind to the TNF receptor. In both situations there is the activation of initiator caspase. The extrinsic pathway can be activated in two ways. The first way is through fast ligan TNF-alpha binding or through a cytotoxic t-cell. The cytotoxic T-cell can attach itself to a membrane, facilitating the release of granzyme B. Granzyme B perforates the target cell membrane and in turn allows the release of perforin. Finally, perforin creates a pore in the membrane, and releases the caspases which leads to the activation of caspase 3. This initiator caspase may cause the cleaving of inactive caspase 3, causing it to become cleaved caspase 3. This is the final molecule needed to trigger cell death.<ref>{{Cite web |title= Apoptosis &#124; Intrinsic and extrinsic pathway &#124; USMLE step 1 &#124; Pathology| website=[[YouTube]] | date=8 January 2023 |url=https://www.youtube.com/watch?v=fwXpI6HdaZo.}}</ref>

===== Intrinsic Pathway =====
The intrinsic pathway is caused by cell damage such as DNA damage or UV exposure. This pathway takes place in the mitochondria and is mediated by sensors called Bcl sensors, and two proteins called BAX and BAK. These proteins are found in a majority of higher mammals as they are able to pierce the mitochondrial outer membrane - making them an integral part of mediating cell death by apoptosis. They do this by orchestrating the formation of pores within the membrane - essential to the release of cytochrome c. However, cytochrome c is only released if the mitochondrial membrane is compromised. Once cytochrome c is detected, the apoptosome complex is formed. This complex activates the executioner caspase which causes cell death. This killing of the cells may be essential as it prevents cellular overgrowth which can result in disease such as cancer. There are another two proteins worth mentioning that inhibit the release of cytochrome c in the mitochondria. Bcl-2 and Bcl-xl are anti-apoptotic and therefore prevent cell death. There is a potential mutation that can occur in that causes the overactivity of Bcl-2. It is the translocation between chromosomes 14 and 18. This over activity can result in the development of follicular lymphoma.<ref>{{Cite web |title=Apoptosis | website=[[YouTube]] | date=30 March 2019 |url=https://www.youtube.com/watch?v=jRZHDhHf3tA}}</ref>

=== Autophagy ===

[[Macroautophagy]], often referred to as [[autophagy]], is a [[catabolic]] process that results in the [[Autophagosome|autophagosomic]]-[[Lysosome|lysosomal]] degradation of bulk [[cytoplasm]]ic contents, abnormal protein aggregates, and excess or damaged [[organelle]]s.{{cn|date=November 2024}}

[[Autophagy]] is generally activated by conditions of [[nutrient]] deprivation but has also been associated with [[Physiology|physiolog]]ical as well as [[Pathology|patholog]]ical processes such as development, differentiation, [[neurodegenerative]] [[disease]]s, [[Stress (physiology)|stress]], [[infection]] and [[cancer]].{{cn|date=November 2024}}

==== Mechanism ====

A critical regulator of autophagy induction is the [[kinase]] [[mTOR]], which when activated, suppresses [[autophagy]] and when not activated promotes it. Three related [[serine]]/[[threonine]] kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast [[Atg1]], act downstream of the [[mTOR]] complex. [[ULK1]] and [[ULK2]] form a large complex with the mammalian [[homolog]] of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, [[BECN1|Beclin-1]], p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy.{{cn|date=November 2024}}

The [[Methionine|ATG]] [[gene]]s control the [[autophagosome]] formation through [[ATG12]]-[[ATG5]] and LC3-II ([[ATG8]]-II) complexes. [[ATG12]] is conjugated to [[ATG5]] in a [[ubiquitin]]-like reaction that requires [[ATG7]] and [[ATG10]]. The Atg12–Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/[[ATG8]] is cleaved at its C terminus by ATG4 [[protease]] to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane.{{cn|date=November 2024}}

[[Autophagy]] and [[apoptosis]] are connected both positively and negatively, and extensive crosstalk exists between the two. During [[Malnutrition|nutrient deficiency]], [[autophagy]] functions as a pro-survival mechanism, however, excessive [[autophagy]] may lead to [[cell death]], a process [[Morphology (biology)|morphologically]] distinct from [[apoptosis]]. Several pro-apoptotic [[Cell signaling|signals]], such as [[TNF]], [[TRAIL]], and [[FADD]], also induce autophagy. Additionally, [[Bcl-2]] inhibits [[BECN1|Beclin-1]]-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.{{cn|date=November 2024}}

===Other types===
{{See also|PANoptosis}}
Besides the above two types of PCD, other pathways have been discovered.<ref>
{{cite journal
 |vauthors=Kroemer G, Martin SJ |year = 2005
 |title = Caspase-independent cell death
 |journal = [[Nature Medicine]]
 |volume = 11 |issue = 7 |pages = 725–30
 |pmid = 16015365
 |doi = 10.1038/nm1263
|s2cid = 8264709
 }}</ref>
Called "non-apoptotic programmed cell-death" (or "[[caspase]]-independent programmed cell-death" or "necroptosis"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD.{{cn|date=November 2024}}

Other forms of programmed cell death include [[anoikis]], almost identical to apoptosis except in its induction; [[cornification]], a form of cell death exclusive to the epidermis; [[excitotoxicity]]; [[ferroptosis]], an iron-dependent form of cell death<ref>{{cite journal |author1=Dixon Scott J. |author2=Lemberg Kathryn M. |author3=Lamprecht Michael R. |author4=Skouta Rachid |author5=Zaitsev Eleina M. |author6=Gleason Caroline E. |author7=Patel Darpan N. |author8=Bauer Andras J. |author9=Cantley Alexandra M. | title = Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death | url= | journal = Cell | volume = 149 | issue = 5| pages = 1060–1072 | doi=10.1016/j.cell.2012.03.042|pmid=22632970 |display-authors=etal|year=2012 |pmc=3367386 }}</ref> and [[Wallerian degeneration]].

[[Necroptosis]] is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via [[apoptosis]]. [[Nemosis]] is another programmed form of necrosis that takes place in [[fibroblasts]].<ref name="bizik2004">{{cite journal |author1=Jozef Bizik |author2=Esko Kankuri |author3=Ari Ristimäki |author4=Alain Taieb |author5=Heikki Vapaatalo |author6=Werner Lubitz |author7=Antti Vaheri |year=2004 |title=Cell-cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression. |journal=Cell Death and Differentiation |volume=11 |issue=2 |pages=183–195 |pmid=14555963 |doi=10.1038/sj.cdd.4401317|doi-access=free }}</ref>

[[Eryptosis]] is a form of suicidal [[erythrocyte]] death.<ref>{{cite journal|last1=Lang|first1=F|last2=Lang|first2=KS|last3=Lang|first3=PA|last4=Huber|first4=SM|last5=Wieder|first5=T|title=Mechanisms and significance of eryptosis.|journal=Antioxidants & Redox Signaling|volume=8|issue=7–8|pages=1183–92|pmid=16910766|doi=10.1089/ars.2006.8.1183|year=2006}}</ref>

Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.<ref>{{cite journal | last1 = Formigli | first1 = L |display-authors=etal  | year = 2000 | title = aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis | journal = Journal of Cellular Physiology | volume = 182 | issue = 1| pages = 41–49 | doi=10.1002/(sici)1097-4652(200001)182:1<41::aid-jcp5>3.0.co;2-7| pmid = 10567915 | s2cid = 20064300 }}</ref>

[[NETosis]] is the process of cell-death generated by neutrophils, resulting in [[Neutrophil extracellular traps|NETs]].<ref>{{cite journal|last1=Fadini|first1=GP|last2=Menegazzo|first2=L|last3=Scattolini|first3=V|last4=Gintoli|first4=M|last5=Albiero|first5=M|last6=Avogaro|first6=A|title=A perspective on NETosis in diabetes and cardiometabolic disorders.|journal=Nutrition, Metabolism, and Cardiovascular Diseases|date=25 November 2015|pmid=26719220|doi=10.1016/j.numecd.2015.11.008|volume=26|issue=1|pages=1–8}}</ref>

[[Paraptosis]] is another type of nonapoptotic cell death that is mediated by [[MAPK]] through the activation of [[Insulin-like growth factor 1 receptor|IGF-1]]. It's characterized by the intracellular formation of vacuoles and swelling of mitochondria.<ref name=":0">{{Cite book|title=Histology: A Text and Atlas|last=Ross|first=Michael|year=2016|isbn=978-1451187427|edition=7th|pages=94|publisher=Wolters Kluwer Health }}</ref>

[[Pyroptosis]], an inflammatory type of cell death, is uniquely mediated by [[caspase 1]], an enzyme not involved in apoptosis, in response to infection by certain microorganisms.<ref name=":0" />

Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.{{cn|date=November 2024}}