Editing Programmed cell death

{{short description|Death of a cell mediated by intracellular program, often as part of development}}
{{For|the protein|Programmed cell death protein 1}}
{{mcn|date=April 2025}}
'''Programmed cell death''' ('''PCD''') sometimes referred to as '''cell, or cellular  suicide'''<ref>{{cite journal|last1=Raff|first1=M|date=12 November 1998|title=Cell suicide for beginners.|journal=Nature|volume=396|issue=6707|pages=119–22|doi=10.1038/24055|issn=0028-0836|pmid=9823889|bibcode=1998Natur.396..119R|s2cid=4341684|doi-access=free}}</ref><ref name="Albert's">{{cite web |last1=Alberts |first1=Bruce |last2=Johnson |first2=Alexander |last3=Lewis |first3=Julian |last4=Raff |first4=Martin |last5=Roberts |first5=Keith |last6=Walter |first6=Peter |title=Programmed Cell Death (Apoptosis) |url=https://www.ncbi.nlm.nih.gov/books/NBK26873/#:~:text=If%20cells%20are%20no%20longer,as%20leaves%20from%20a%20tree). |website=Molecular Biology of the Cell. 4th edition |publisher=Garland Science |access-date=12 April 2025 |language=en |date=2002}}</ref><ref name="Genome2025">{{cite web |title=Apoptosis |url=https://www.genome.gov/genetics-glossary/apoptosis |website=www.genome.gov |access-date=12 April 2025 |language=en}}</ref> is the [[death]] of a [[cell (biology)|cell]] as a result of events inside of a cell, such as [[apoptosis]] or [[autophagy]].<ref>{{cite journal
 |vauthors    = Engelberg-Kulka H, Amitai S, Kolodkin-Gal I, Hazan R
 |year        = 2006
 |title       = Bacterial Programmed Cell Death and Multicellular Behavior in Bacteria
 |journal     = [[PLOS Genetics]]
 |volume      = 2
 |issue       = 10
 |pages       = e135
 |doi         = 10.1371/journal.pgen.0020135
 |pmid        = 17069462
 |pmc         = 1626106
|doi-access = free
 }}
</ref><ref>{{cite book|last=Green|first=Douglas|title=Means To An End|year=2011|publisher=Cold Spring Harbor Laboratory Press|location=New York|isbn=978-0-87969-887-4|url=http://celldeathbook.wordpress.com/}}</ref> PCD is carried out in a [[biological process]], which usually confers advantage during an organism's [[biological life cycle|lifecycle]]. For example, the [[Limb development|differentiation of fingers and toes]] in a developing human embryo occurs because cells between the fingers [[apoptose]]; the result is that the digits are separate. PCD serves fundamental functions during both [[plant]] and [[animal]] tissue development.

Apoptosis and autophagy are both forms of programmed cell death.<ref name=":1">{{cite book|last=Kierszenbaum|first=Abraham|title=Histology and Cell Biology - An Introduction to Pathology|publisher=ELSEVIER SAUNDERS|year=2012|location=Philadelphia}}</ref> [[Necrosis]] is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Necrosis was long seen as a non-physiological process that occurs as a result of infection or injury,<ref name=":1" /> but in the 2000s, a form of programmed necrosis, called [[necroptosis]],<ref>{{Cite journal|title = Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury|journal = Nature Chemical Biology|date = 2005-07-01|issn = 1552-4450|pmid = 16408008|pages = 112–119|volume = 1|issue = 2|doi = 10.1038/nchembio711|first1 = Alexei|last1 = Degterev|first2 = Zhihong|last2 = Huang|first3 = Michael|last3 = Boyce|first4 = Yaqiao|last4 = Li|first5 = Prakash|last5 = Jagtap|first6 = Noboru|last6 = Mizushima|first7 = Gregory D.|last7 = Cuny|first8 = Timothy J.|last8 = Mitchison|first9 = Michael A.|last9 = Moskowitz|s2cid = 866321}}</ref> was recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.<ref>
{{cite journal
 |vauthors=Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P |year=2014
 |title=Regulated necrosis: the expanding network of non-apoptotic cell death pathways
 |journal=[[Nat Rev Mol Cell Biol]]
 |volume=15 |issue=2 |pages=135–147
 |doi=10.1038/nrm3737
 |pmid=24452471
|s2cid=13919892
 }}</ref>

==History==
The concept of "programmed cell-death" was used by [[Richard A. Lockshin|Lockshin]] & Williams<ref name="insect">
{{cite journal
 |vauthors=Lockshin RA, Williams CM |year=1964
 |title=Programmed cell death—II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths
 |journal=Journal of Insect Physiology
 |volume=10 |issue=4 |pages=643–649
 |doi=10.1016/0022-1910(64)90034-4
|bibcode=1964JInsP..10..643L
 }}</ref> in 1964 in relation to [[insect]] tissue development, around eight years before "apoptosis" was coined. The term PCD has, however, been a source of confusion and Durand and Ramsey<ref>{{Cite journal|last=Durand and Ramsey|first=Pierre M. and Grant|date=2019|title=The nature of programmed cell death|journal=Biological Theory|volume=14|pages=30–41|doi=10.1007/s13752-018-0311-0|s2cid=91622808|url=http://philsci-archive.pitt.edu/15344/1/PCD_Preprint.pdf}}</ref> have developed the concept by providing mechanistic and evolutionary definitions. PCD has become the general terms that refers to all the different types of cell death that have a genetic component.{{cn|date=November 2024}}

The first insight into the mechanism came from studying [[BCL2]], the product of a putative [[oncogene]] activated by [[chromosome]] [[Chromosomal translocation|translocation]]s often found in follicular [[lymphoma]]. Unlike other cancer genes, which promote [[cancer]] by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves.<ref name="pmid3262202">{{cite journal |vauthors=Vaux DL, Cory S, Adams JM | title = Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells | journal = Nature | volume = 335 | issue = 6189 | pages = 440–2 |date=September 1988 | pmid = 3262202 | doi = 10.1038/335440a0 | bibcode = 1988Natur.335..440V | s2cid = 23593952 }}</ref>

PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 [[Nobel Prize in Physiology or Medicine]] to [[Sydney Brenner]] ([[United Kingdom]]), [[H. Robert Horvitz]] (US) and [[John E. Sulston]] (UK).<ref>
{{cite web
 |title = The Nobel Prize in Physiology or Medicine 2002
 |url = http://nobelprize.org/nobel_prizes/medicine/laureates/2002/index.html
 |publisher = [[The Nobel Foundation]]
 |year = 2002
 |access-date = 2009-06-21
}}</ref>

==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}}

== Atrophic factors ==

An atrophic factor is a force that causes a [[cell (biology)|cell]] to [[Atrophy|die]]. Only natural forces on the cell are considered to be atrophic factors, whereas, for example, agents of mechanical or chemical abuse or lysis of the cell are considered not to be atrophic factors. Common types of atrophic factors are:<ref>[http://www.psycheducation.org/mechanism/10AllPlayers.htm Chapter 10:  All the Players on One Stage] {{Webarchive|url=https://web.archive.org/web/20130528172823/http://www.psycheducation.org/mechanism/10AllPlayers.htm |date=2013-05-28 }} from PsychEducation.org</ref>

# Decreased workload
# Loss of innervation
# Diminished blood supply
# Inadequate nutrition
# Loss of [[endocrine]] stimulation
# Senility
# Compression

==Role in the development of the nervous system==
[[File:Dying cells in the proliferative zone.jpg|thumb|right|Dying cells in the proliferate zone]]

The initial expansion of the developing [[nervous system]] is counterbalanced by the removal of neurons and their processes.<ref name="Tau">{{cite journal|last=Tau|first=GZ|title=Normal development of brain circuits|journal=Neuropsychopharmacology|year=2009|volume=35|issue=1|pages=147–168|doi=10.1038/npp.2009.115|pmid=19794405|pmc=3055433}}</ref> During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).<ref name="Dekkers">{{cite journal|last=Dekkers|first=MP|title=Death of developing neurons: new insights and implications for connectivity|journal=Journal of Cell Biology|year=2013|volume=203|pages=385–393|doi=10.1083/jcb.201306136 |pmid=24217616|issue=3|pmc=3824005}}</ref> PCD in the nervous system was first recognized in 1896 by John Beard.<ref name="Oppenheim 1981">{{cite book|last=Oppenheim|first=RW|title=Neuronal cell death and some related regressive phenomena during neurogenesis: a selective historical review and progress report|year=1981|publisher=Oxford University Press|location=In Studies in Developmental Neurobiology: Essays in Honor of Viktor Hamburger|pages=74–133}}</ref> Since then several theories were proposed to understand its biological significance during [[neural development]].<ref name="Buss">{{cite journal|last=Buss|first=RR|title=Adaptive roles of programmed cell death during nervous system development|journal=Annual Review of Neuroscience|year=2006|volume=29|pages=1–35|doi=10.1146/annurev.neuro.29.051605.112800|pmid=16776578}}</ref>

===Role in neural development===
PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells.<ref name="Tau" /> One theory suggests that PCD is an adaptive mechanism to regulate the number of [[progenitor cells]]. In humans, PCD in progenitor cells starts at gestational week 7 and remains until the first trimester.<ref name="De la rosa">{{cite journal|last=De la Rosa|first=EJ|author2=De Pablo, F|title=Cell death in early neural development: beyond the neurotrophic theory|journal=Trends in Neurosciences|date=October 23, 2000|volume=23|issue=10|pages=454–458|doi=10.1016/s0166-2236(00)01628-3|pmid=11006461|s2cid=10493404}}</ref> This process of cell death has been identified in the germinal areas of the [[cerebral cortex]], [[cerebellum]], [[thalamus]], [[brainstem]], and [[spinal cord]] among other regions.<ref name="Buss" /> At gestational weeks 19–23, PCD is observed in post-mitotic cells.<ref name="Lossiand Merighi">{{cite journal|last=Lossi|first=L|author2=Merighi, A|title=In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS|journal=Progress in Neurobiology|date=April 2003|volume=69|issue=5|pages=287–312|doi=10.1016/s0301-0082(03)00051-0|pmid=12787572|s2cid=27052883}}</ref> The prevailing theory explaining this observation is the neurotrophic theory which states that PCD is required to optimize the connection between neurons and their afferent inputs and efferent targets.<ref name="Buss" /> Another theory proposes that developmental PCD in the nervous system occurs in order to correct for errors in neurons that have migrated ectopically, innervated incorrect targets, or have [[axons]] that have gone awry during path finding.<ref name="Finlay">{{cite journal|last=Finlay|first=BL|title=Control of cell number in the developing mammalian visual system|journal=Progress in Neurobiology|year=1989|volume=32|issue=3|pages=207–234|doi=10.1016/0301-0082(89)90017-8|pmid=2652194|s2cid=2788103}}</ref> It is possible that PCD during the development of the nervous system serves different functions determined by the developmental stage, cell type, and even species.<ref name="Buss" />

===The neurotrophic theory===
The neurotrophic theory is the leading hypothesis used to explain the role of programmed cell death in the developing nervous system.<ref>{{Cite journal|last1=Yamaguchi|first1=Yoshifumi|last2=Miura|first2=Masayuki|date=2015-02-23|title=Programmed Cell Death in Neurodevelopment|journal=Developmental Cell|language=en|volume=32|issue=4|pages=478–490|doi=10.1016/j.devcel.2015.01.019|issn=1534-5807|pmid=25710534|doi-access=free}}</ref> It postulates that in order to ensure optimal innervation of targets, a surplus of neurons is first produced which then compete for limited quantities of protective [[neurotrophic factors]] and only a fraction survive while others die by programmed cell death.<ref name="De la rosa" /> Furthermore, the theory states that predetermined factors regulate the amount of neurons that survive and the size of the innervating neuronal population directly correlates to the influence of their target field.<ref name="Patterning PNS">{{cite book|last=Rubenstein|first=John|title=Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience|year=2013|publisher=Academic Press|isbn=978-0-12-397348-1|author2=Pasko Rakic|chapter=Regulation of Neuronal Survival by Neurotrophins in the Developing Peripheral Nervous System}}</ref>

The underlying idea that target cells secrete attractive or inducing factors and that their [[growth cone]]s have a [[chemotactic]] sensitivity was first put forth by [[Santiago Ramon y Cajal]] in 1892.<ref name="Sotelo">{{cite book|last=Constantino|first=Sotelo|title=Changing Views of Cajal's Neuron |chapter=Chapter 2 the chemotactic hypothesis of Cajal: A century behind |series=Progress in Brain Research|year=2002|volume=136|pages=11–20|doi=10.1016/s0079-6123(02)36004-7|pmid=12143376|isbn=9780444508157}}</ref> Cajal presented the idea as an explanation for the "intelligent force" axons appear to take when finding their target but admitted that he had no empirical data.<ref name="Sotelo" /> The theory gained more attraction when experimental manipulation of axon targets yielded death of all innervating neurons. This developed the concept of target derived regulation which became the main tenet in the neurotrophic theory.<ref name="Oppenheim 2">{{cite journal|last=Oppenheim|first=Ronald|title=The neurotrophic theory and naturally occurring motorneuron death|journal=Trends in Neurosciences|year=1989|volume=12|issue=7|pages=252–255|doi=10.1016/0166-2236(89)90021-0|pmid=2475935|s2cid=3957751}}</ref><ref name="Death in developing">{{cite journal|last1=Dekkers|first1= MP|last2= Nikoletopoulou |first2=V|last3= Barde|first3= YA|title=Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity|journal=J Cell Biol|date=November 11, 2013|volume=203|issue=3|pages=385–393|doi=10.1083/jcb.201306136|pmid=24217616|pmc=3824005}}</ref> Experiments that further supported this theory led to the identification of the first neurotrophic factor, [[nerve growth factor]] (NGF).<ref name="Cowan">{{cite journal|last=Cowan|first=WN|title=Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor|journal=Annual Review of Neuroscience|year=2001|volume=24|pages=551–600|doi=10.1146/annurev.neuro.24.1.551|pmid=11283321|s2cid=6747529}}</ref>

===Peripheral versus central nervous system===
[[File:Programmed cell death in the peripheral and central nervous system.jpg|thumb|right|Cell death in the peripheral vs central nervous system]]

Different mechanisms regulate PCD in the [[peripheral nervous system]] (PNS) versus the [[central nervous system]] (CNS). In the PNS, innervation of the target is proportional to the amount of the target-released neurotrophic factors NGF and [[NT3]].<ref name="Weltman">{{cite journal|last=Weltman|first=JK|title=The 1986 Nobel Prize for Physiology or Medicine awarded for discovery of growth factors: Rita Levi-Montalcini, M.D., and Stanley Cohen, Ph.D.|journal=New England Regional Allergy Proceedings|date=February 8, 1987|pmid=3302667|doi=10.2500/108854187779045385|volume=8|issue=1|pages=47–8}}</ref><ref name="Dekkers1">{{cite journal|last=Dekkers|first=M|title=Programmed Cell Death in Neuronal Development|journal=Science|date=April 5, 2013|volume=340|issue=6128|pages=39–41|doi=10.1126/science.1236152|pmid=23559240|bibcode=2013Sci...340...39D|s2cid=206548254}}</ref> Expression of neurotrophin receptors, [[TrkA]] and [[TrkC]], is sufficient to induce [[apoptosis]] in the absence of their [[ligands]].<ref name="Dekkers" /> Therefore, it is speculated that PCD in the PNS is dependent on the release of neurotrophic factors and thus follows the concept of the neurotrophic theory.{{cn|date=November 2024}}

Programmed cell death in the CNS is not dependent on external [[growth factors]] but instead relies on intrinsically derived cues. In the [[neocortex]], a 4:1 ratio of excitatory to inhibitory [[interneurons]] is maintained by apoptotic machinery that appears to be independent of the environment.<ref name="Dekkers1" /> Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured [[in vitro]].<ref name="Southwell">{{cite journal|last=Southwell|first=D.G.|title=Intrinsically determined cell death of developing cortical interneurons|journal=Nature|date=November 2012|volume=491|issue=7422|pages=109–115|doi=10.1038/nature11523|pmid=23041929|pmc=3726009|bibcode=2012Natur.491..109S}}</ref> Transplanted cells died at the age of two weeks, the same age at which endogenous interneurons undergo apoptosis. Regardless of the size of the transplant, the fraction of cells undergoing apoptosis remained constant. Furthermore, disruption of [[TrkB]], a receptor for [[brain derived neurotrophic factor]] (Bdnf), did not affect cell death. It has also been shown that in mice null for the proapoptotic factor [[Bcl-2-associated X protein|Bax]] (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice.<ref name="Southwell" /> Together these findings indicate that programmed cell death in the CNS partly exploits Bax-mediated signaling and is independent of BDNF and the environment. Apoptotic mechanisms in the CNS are still not well understood, yet it is thought that apoptosis of interneurons is a self-autonomous process.{{cn|date=November 2024}}

===Nervous system development in its absence===
Programmed cell death can be reduced or eliminated in the developing nervous system by the targeted deletion of pro-apoptotic genes or by the overexpression of anti-apoptotic genes. The absence or reduction of PCD can cause serious anatomical malformations but can also result in minimal consequences depending on the gene targeted, neuronal population, and stage of development.<ref name="Buss" /> Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in [[caspase-3]] or [[caspase-9]] [[knockout mice]] which develop [[exencephaly]] in the [[forebrain]].<ref name="Kuida">{{cite journal|last=Kuida|first=K|title=Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9|journal=Cell|year=1998|volume=94|issue=3|pages=325–337|doi=10.1016/s0092-8674(00)81476-2|pmid=9708735|s2cid=8417446|doi-access=free}}</ref><ref name="Kuida decreased">{{cite journal|last=Kuida|first=K|title=Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice|journal=Nature|year=1996|volume=384|pages=368–372|doi=10.1038/384368a0|issue=6607|pmid=8934524|bibcode=1996Natur.384..368K|s2cid=4353931}}</ref> The brainstem, spinal cord, and peripheral ganglia of these mice develop normally, however, suggesting that the involvement of [[caspases]] in PCD during development depends on the brain region and cell type.<ref name="Oppenheim caspase">{{cite journal|last=Oppenheim|first=RW|title=Programmed cell death of developing mammalian neurons after genetic deletion of caspases|journal=Journal of Neuroscience|year=2001|volume=21|issue=13|pages=4752–4760|doi=10.1523/JNEUROSCI.21-13-04752.2001|pmid=11425902|pmc=6762357|doi-access=free}}</ref> Knockout or inhibition of apoptotic protease activating factor 1 ([[APAF1]]), also results in malformations and increased embryonic lethality.<ref name="Cecconi">{{cite journal|last=Cecconi|first=F|title=Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development|journal=Cell|year=1998|volume=94|issue=6|pages=727–737|doi=10.1016/s0092-8674(00)81732-8|pmid=9753320|doi-access=free}}</ref><ref name="Hao">{{cite journal|last=Hao|first=Z|title=Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis|journal=Cell|year=2005|volume=121|issue=4|pages=579–591|doi=10.1016/j.cell.2005.03.016|pmid=15907471|s2cid=4921039|doi-access=free}}</ref><ref name="Yoshida">{{cite journal|last=Yoshida|first=H|title=Apaf1 is required for mitochondrial pathways of apoptosis and brain development|journal=Cell|year=1998|volume=94|issue=6|pages=739–750|doi=10.1016/s0092-8674(00)81733-x|pmid=9753321|s2cid=1096066|doi-access=free}}</ref> Manipulation of apoptosis regulator proteins [[Bcl-2]] and Bax (overexpression of Bcl-2 or deletion of Bax) produces an increase in the number of neurons in certain regions of the nervous system such as the [[retina]], [[trigeminal nucleus]], cerebellum, and spinal cord.<ref name="Bonfanti">{{cite journal|last=Bonfanti|first=L|title=Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2|journal=Journal of Neuroscience|year=1996|volume=16|issue=13|pages=4186–4194|doi=10.1523/JNEUROSCI.16-13-04186.1996|pmid=8753880|pmc=6578989|doi-access=free}}</ref><ref name="Martinou">{{cite journal|last=Martinou|first=JC|title=Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia|journal=Neuron|year=1994|volume=13|issue=4|pages=1017–1030|doi=10.1016/0896-6273(94)90266-6|pmid=7946326|s2cid=25546670}}</ref><ref name="Zanjani">{{cite journal|last=Zanjani|first=HS|title=Increased cerebellar Purkinje cell numbers in mice overexpressing a human bcl-2 transgene|journal=Journal of Computational Neurology|year=1996|volume=374|issue=3|pages=332–341|doi=10.1002/(sici)1096-9861(19961021)374:3<332::aid-cne2>3.0.co;2-2|pmid=8906502|s2cid=32460867 }}</ref><ref name="Zup">{{cite journal|last=Zup|first=SL|title=Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord|journal=Journal of Neuroscience|year=2003|volume=23|issue=6|pages=2357–2362|doi=10.1523/JNEUROSCI.23-06-02357.2003|pmid=12657695|pmc=6742046|doi-access=free}}</ref><ref name="Fan">{{cite journal|last=Fan|first=H|title=Elimination of Bax expression in mice increases cerebellar Purkinje cell numbers but not the number of granule cells|journal=Journal of Computational Neurology|year=2001|volume=436|issue=1|pages=82–91|doi=10.1002/cne.1055.abs|pmid=11413548}}</ref><ref name="Mosinger">{{cite journal|last=Mosinger|first=Ogilvie|title=Suppression of developmental retinal cell death but not of photoreceptor degeneration in Bax-deficient mice|journal=Investigative Ophthalmology & Visual Science|year=1998|volume=39|pages=1713–1720}}</ref><ref name="White">{{cite journal|last=White|first=FA|title=Widespread elimination of naturally occurring neuronal death in Bax-deficient mice|journal=Journal of Neuroscience|year=1998|volume=18|issue=4|pages=1428–1439|doi=10.1523/JNEUROSCI.18-04-01428.1998|pmid=9454852|pmc=6792725|doi-access=free}}</ref> However, PCD of neurons due to Bax deletion or Bcl-2 overexpression does not result in prominent morphological or behavioral abnormalities in mice. For example, mice overexpressing Bcl-2 have generally normal motor skills and vision and only show impairment in complex behaviors such as learning and anxiety.<ref name="Gianfranceschi">{{cite journal|last=Gianfranceschi|first=L|title=Behavioral visual acuity of wild type and bcl2 transgenic mouse|journal=Vision Research|year=1999|volume=39|issue=3|pages=569–574|doi=10.1016/s0042-6989(98)00169-2|pmid=10341985|s2cid=5544203|doi-access=free}}</ref><ref name="Rondi">{{cite journal|last=Rondi-Reig|first=L|title=To die or not to die, does it change the function? Behavior of transgenic mice reveals a role for developmental cell death|journal=Brain Research Bulletin|year=2002|volume=57|issue=1|pages=85–91|doi=10.1016/s0361-9230(01)00639-6|pmid=11827740|s2cid=35145189}}</ref><ref name="Rondi Transgenic Mice">{{cite journal|last=Rondi-Reig|first=L|title=Transgenic mice with neuronal overexpression of bcl-2 gene present navigation disabilities in a water task|journal=Neuroscience|year=2001|volume=104|issue=1|pages=207–215|doi=10.1016/s0306-4522(01)00050-1|pmid=11311543|s2cid=30817916}}</ref> The normal behavioral [[phenotypes]] of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.<ref name="Buss" />

===Invertebrates and vertebrates===
[[File:A conserved apoptotic pathway in nematodes, mammals and fruitflies.jpg|thumb|right|A conserved apoptotic pathway in nematodes, mammals and fruitflies]]

Learning about PCD in various species is essential in understanding the evolutionary basis and reason for apoptosis in development of the nervous system. During the development of the [[invertebrate]] nervous system, PCD plays different roles in different species.<ref>{{Cite journal|last1=Buss|first1=Robert R.|last2=Sun|first2=Woong|last3=Oppenheim|first3=Ronald W.|title=Adaptive Roles of Programmed Cell Death During Nervous System Development|date=2006-07-21|journal=Annual Review of Neuroscience|volume=29|issue=1|pages=1–35|doi=10.1146/annurev.neuro.29.051605.112800|pmid=16776578|issn=0147-006X}}</ref> The similarity of the asymmetric cell death mechanism in the [[nematode]] and the [[leech]] indicates that PCD may have an evolutionary significance in the development of the nervous system.<ref name="Sulston">{{cite journal|last=Sulston|first=JE|title=The Caenorhabditis elegans male: postembryonic development of nongonadal structures|journal=Developmental Biology|year=1980|volume=78|issue=2|pages=542–576|doi=10.1016/0012-1606(80)90352-8|pmid=7409314}}</ref> In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages.<ref name="Sulston1">{{cite journal|last=Sulston2|first=JE|title=The embryonic cell lineage of the nematode Caenorhabditis elegans|journal=Developmental Biology|year=1983|volume=100|pages=64–119|doi=10.1016/0012-1606(83)90201-4|pmid=6684600|issue=1}}</ref> Cell death in [[arthropods]] occurs first in the nervous system when [[ectoderm]] cells differentiate and one daughter cell becomes a [[neuroblast]] and the other undergoes apoptosis.<ref name="Doe">{{cite journal|last=Doe|first=Cq|title=Development and segmental differences in the pattern of neuronal precursor cells|journal=Journal of Developmental Biology|year=1985|volume=111|issue=1|pages=193–205|doi=10.1016/0012-1606(85)90445-2|pmid=4029506}}</ref> Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.<ref name="Giebultowicz">{{cite journal|last=Giebultowicz|first=JM|title=Sexual differentiation in the terminal ganglion of the moth Manduca sexta: role of sex-specific neuronal death|journal=Journal of Comparative Neurology|year=1984|volume=226|issue=1|pages=87–95|doi=10.1002/cne.902260107|pmid=6736297|s2cid=41793799}}</ref> In ''[[Drosophila]]'', PCD is essential in segmentation and specification during development.{{cn|date=November 2024}}

In contrast to invertebrates, the mechanism of programmed cell death is found to be more conserved in [[vertebrates]]. Extensive studies performed on various vertebrates show that PCD of neurons and [[glia]] occurs in most parts of the nervous system during development. It has been observed before and during [[synaptogenesis]] in the central nervous system as well as the peripheral nervous system.<ref name="Buss" /> However, there are a few differences between vertebrate species. For example, [[mammals]] exhibit extensive arborization followed by PCD in the retina while birds do not.<ref name="Cook">{{cite journal|last=Cook|first=B|title=Developmental neuronal death is not a universal phenomenon among cell types in the chick embryo retina|journal=Journal of Comparative Neurology|year=1998|volume=396|issue=1|pages=12–19|doi=10.1002/(sici)1096-9861(19980622)396:1<12::aid-cne2>3.0.co;2-l|pmid=9623884|s2cid=25569721}}</ref> Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.<ref name="Buss" />

==In plant tissue==
Programmed cell death in plants has a number of molecular similarities to animal [[apoptosis]], but it also has differences, the most obvious being the presence of a [[cell wall]] and the lack of an [[immune system]] that removes the pieces of the dead cell.  Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a [[vacuole]] that ruptures as the cell dies.<ref>
{{cite journal
 |vauthors    = Collazo C, Chacón O, Borrás O
 |year        = 2006
 |title       = Programmed cell death in plants resembles apoptosis of animals
 |url         = http://elfosscientiae.cigb.edu.cu/PDFs/BA/2006/23/1/BA002301RV001-010.pdf
 |journal     = [[Biotecnología Aplicada]]
 |volume      = 23
 |pages       = 1–10
 |url-status     = dead
 |archive-url  = https://web.archive.org/web/20120314132513/http://elfosscientiae.cigb.edu.cu/PDFs/BA/2006/23/1/BA002301RV001-010.pdf
 |archive-date = 2012-03-14
}}</ref>

In "APL regulates vascular tissue identity in [[Arabidopsis thaliana|Arabidopsis]]",<ref>
{{cite journal
 |vauthors=Bonke M, Thitamadee S, Mähönen AP, Hauser MT, Helariutta Y |year = 2003
 |title = APL regulates vascular tissue identity in Arabidopsis
 |journal = [[Nature (journal)|Nature]]
 |volume = 426 |issue = 6963 |pages = 181–6
 |pmid = 14614507
 |doi = 10.1038/nature02100
|bibcode = 2003Natur.426..181B
 |s2cid = 12672242
 }}</ref> Martin Bonke and his colleagues had stated that one of the two long-distance transport systems in [[vascular plants]], [[xylem]], consists of several cell-types "the differentiation of which involves deposition of elaborate [[Cell wall|cell-wall]] thickenings and programmed cell-death." The authors emphasize that the products of plant PCD play an important structural role.{{cn|date=November 2024}}

Basic morphological and biochemical features of PCD have been conserved in both plant and animal [[Kingdom (biology)|kingdoms]].<ref>
{{cite journal
 |vauthors=Solomon M, Belenghi B, Delledonne M, Menachem E, Levine A |year = 1999
 |title = The involvement of cysteine proteases and protease inhibitor genes in the regulation of programmed cell death in plants
 |journal = [[The Plant Cell]]
 |volume = 11 |issue = 3 |pages = 431–44
 |pmid = 10072402
 |pmc = 144188
 |doi = 10.2307/3870871
 |jstor=3870871
|bibcode = 1999PlanC..11..431S
 }} See also related articles in  [http://www.plantcell.org/ ''The Plant Cell Online'']</ref> Specific types of plant cells carry out unique cell-death programs. These have common features with animal apoptosis—for instance, [[nuclear DNA]] degradation—but they also have their own peculiarities, such as [[Cell nucleus|nuclear]] degradation triggered by the collapse of the [[vacuole]] in [[Tracheid|tracheary]] elements of the xylem.<ref>
{{cite journal
 |vauthors=Ito J, Fukuda H |year = 2002
 |title = ZEN1 Is a Key Enzyme in the Degradation of Nuclear DNA during Programmed Cell Death of Tracheary Elements
 |journal = [[The Plant Cell]]
 |volume = 14 | issue = 12 | pages = 3201–11
 |pmid = 12468737
 |pmc = 151212
 |doi = 10.1105/tpc.006411
|bibcode = 2002PlanC..14.3201I
 }}</ref>

Janneke Balk and Christopher J. Leaver, of the Department of [[Department of Plant Sciences, University of Oxford|Plant Sciences]], [[University of Oxford]], carried out research on mutations in the [[mitochondrial genome]] of [[Sunflower|sun-flower]] cells. Results of this research suggest that [[mitochondria]] play the same key role in vascular plant PCD as in other [[Eukaryote|eukaryotic]] cells.<ref>
{{cite journal
 |vauthors=Balk J, Leaver CJ |year = 2001
 |title = The PET1-CMS Mitochondrial Mutation in Sunflower Is Associated with Premature Programmed Cell Death and Cytochrome c Release
 |journal = [[The Plant Cell]]
 |volume = 13 | issue = 8 | pages = 1803–18
 |pmid = 11487694
 |pmc = 139137
 |doi = 10.1105/tpc.010116
|bibcode = 2001PlanC..13.1803B
 }}</ref>

===PCD in pollen prevents inbreeding===
During [[pollination]], plants enforce [[Self-incompatibility in plants|self-incompatibility]] ('''SI''') as an important means to prevent [[Biological reproduction|self-fertilization]]. Research on the [[corn poppy]] (''Papaver rhoeas'') has revealed that [[protein]]s in the [[pistil]] on which the [[pollen]] lands, interact with pollen and trigger PCD in incompatible (i.e., ''self'') pollen. The researchers, Steven G. Thomas and [[Vernonica Franklin-Tong|Vernonica E. Franklin-Tong]], also found that the response involves rapid inhibition of [[Pollen tube|pollen-tube]] growth, followed by PCD.<ref>
{{cite journal
 |vauthors=Thomas SG, Franklin-Tong VE |year = 2004
 |title = Self-incompatibility triggers programmed cell death in Papaver pollen
 |journal = [[Nature (journal)|Nature]]
 |volume = 429 |issue = 6989 |pages = 305–9
 |pmid = 15152254
 |doi = 10.1038/nature02540
|bibcode = 2004Natur.429..305T
 |s2cid = 4376774
 }}</ref>

==In slime molds==
The social [[Slime mould|slime mold]] ''[[Dictyostelium discoideum]]'' has the peculiarity of either adopting a predatory [[amoeboid|amoeba]]-like behavior in its [[Microorganism|unicellular]] form or coalescing into a mobile [[slug]]-like form when dispersing the [[spore]]s that will give birth to the next [[generation]].<ref>
{{cite journal
 |vauthors=Crespi B, Springer S |year = 2003
 |title = Ecology. Social slime molds meet their match
 |journal = [[Science (journal)|Science]]
 |volume = 299 |issue = 5603 |pages = 56–7
 |pmid = 12511635
 |doi = 10.1126/science.1080776
|s2cid = 83917994
 }}</ref>

The stalk is composed of dead cells that have undergone a type of PCD that shares many features of an autophagic cell-death: massive vacuoles forming inside cells, a degree of [[chromatin]] condensation, but no [[Restriction digest|DNA fragmentation]].<ref>
{{cite journal
 |vauthors=Levraud JP, Adam M, Luciani MF, de Chastellier C, Blanton RL, Golstein P |year = 2003
 |title = Dictyostelium cell death: early emergence and demise of highly polarized paddle cells
 |journal = [[Journal of Cell Biology]]
 |volume = 160 | issue = 7 | pages = 1105–14
 |pmid = 12654899
 |pmc = 2172757
 |doi = 10.1083/jcb.200212104
}}</ref> The structural role of the residues left by the dead cells is reminiscent of the products of PCD in plant tissue.{{cn|date=November 2024}}

''D. discoideum'' is a slime mold, part of a branch that might have emerged from [[Eukaryote|eukaryotic]] ancestors about a [[Timeline of evolution|billion years]] before the present. It seems that they emerged after the ancestors of [[Viridiplantae|green plants]] and the ancestors of [[fungi]] and animals had differentiated. But, in addition to their place in the evolutionary [[Phylogenetic tree|tree]], the fact that PCD has been observed in the humble, simple, six-[[chromosome]] ''D. discoideum'' has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis.<ref>
{{cite journal
 |vauthors=Roisin-Bouffay C, Luciani MF, Klein G, Levraud JP, Adam M, Golstein P |year = 2004
 |title = Developmental cell death in dictyostelium does not require paracaspase
 |journal = [[Journal of Biological Chemistry]]
 |volume = 279 | issue = 12 | pages = 11489–94
 |pmid = 14681218
 |doi = 10.1074/jbc.M312741200
|doi-access = free
 }}</ref>

==Evolutionary origin of mitochondrial apoptosis==
{{Further|Symbiogenesis}}
The occurrence of programmed cell death in [[protist]]s is possible,<ref>{{cite journal | last1 = Deponte | first1 = M | year = 2008 | title = Programmed cell death in protists | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1783 | issue = 7| pages = 1396–1405 | doi=10.1016/j.bbamcr.2008.01.018| pmid = 18291111 | doi-access = free }}</ref><ref>Kaczanowski S, Sajid M and Reece S E 2011 Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites Parasites Vectors 4 44</ref> but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.<ref>{{cite journal | last1 = Proto | first1 = W. R. | last2 = Coombs | first2 = G. H. | last3 = Mottram | first3 = J. C. | year = 2012 | title = Cell death in parasitic protozoa: regulated or incidental? | url = http://www.gla.ac.uk/media/media_248886_en.pdf | journal = Nature Reviews Microbiology | volume = 11 | issue = 1 | pages = 58–66 | doi = 10.1038/nrmicro2929 | pmid = 23202528 | s2cid = 1633550 | access-date = 2014-11-14 | archive-url = https://web.archive.org/web/20160303235943/http://www.gla.ac.uk/media/media_248886_en.pdf | archive-date = 2016-03-03 | url-status = dead }}</ref><ref>{{cite journal | title=Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites | author=Szymon Kaczanowski | author2=Mohammed Sajid | author3=Sarah E Reece | journal=Parasites & Vectors | year=2011 | volume=4 | pages=44 | doi=10.1186/1756-3305-4-44| pmid=21439063 | pmc=3077326 | doi-access=free }}</ref>

Biologists had long suspected that [[mitochondria]] originated from [[bacteria]] that had been incorporated as [[endosymbiont]]s ("living together inside") of larger eukaryotic cells. It was [[Lynn Margulis]] who from 1967 on championed this [[theory]], which has since become widely accepted.<ref>{{cite journal|author=de Duve C|author-link=Christian de Duve|year=1996|title=The birth of complex cells|journal=[[Scientific American]]|volume=274|issue=4|pages=50–7|pmid=8907651|doi=10.1038/scientificamerican0496-50|bibcode=1996SciAm.274d..50D}}</ref> The most convincing [[evidence]] for this theory is the fact that mitochondria possess their own [[DNA]] and are equipped with [[gene]]s and [[DNA replication|replication]] apparatus.{{cn|date=November 2024}}

This [[evolution]]ary step would have been risky for the primitive eukaryotic cells, which began to engulf the [[Electron transport chain|energy-producing]] bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic [[Host (biology)|hosts]]. This process is still evident today, between [[human]] white [[White blood cell|blood cells]] and bacteria. Most of the time, invading bacteria are destroyed by the white blood cells; however, it is not uncommon for the [[chemical warfare]] waged by [[prokaryote]]s to succeed, with the consequence known as [[infection]] by its resulting damage.{{cn|date=November 2024}}

One of these rare evolutionary events, about [[Timeline of evolution|two billion years]] before the present, made it possible for certain eukaryotes and energy-producing prokaryotes to coexist and mutually benefit from their [[symbiosis]].<ref>{{cite journal|vauthors=Dyall SD, Brown MT, Johnson PJ |year=2004|title=Ancient invasions: from endosymbionts to organelles|journal=[[Science (journal)|Science]]|volume=304|issue=5668|pages=253–7|pmid=15073369|doi=10.1126/science.1094884|bibcode=2004Sci...304..253D|s2cid=19424594}}</ref>

Mitochondriate eukaryotic cells live poised between [[life]] and death, because mitochondria still retain their repertoire of [[molecule]]s that can trigger cell suicide.<ref>{{cite journal|vauthors=Chiarugi A, Moskowitz MA |year=2002|title=Cell biology. PARP-1--a perpetrator of apoptotic cell death?|journal=[[Science (journal)|Science]]|volume=297|issue=5579|pages=200–1|pmid= 12114611|doi=10.1126/science.1074592|s2cid=82828773}}</ref> It is not clear why apoptotic machinery is maintained in the extant unicellular organisms. This process has now been evolved to happen only when programmed.<ref>Kaczanowski, S. Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging. Phys Biol 13, http://iopscience.iop.org/article/10.1088/1478-3975/13/3/031001</ref> to cells (such as feedback from neighbors, stress or [[DNA repair|DNA damage]]), mitochondria release [[caspase]] activators that trigger the cell-death-inducing [[Biochemistry|biochemical]] cascade. As such, the cell suicide [[Reaction mechanism|mechanism]] is now crucial to all of our lives.{{cn|date=November 2024}}

==DNA damage and apoptosis==

[[File:DNA damage can lead to apoptosis or cancer.jpg|thumb|500px|Oxidative stress or environmental insults can lead to DNA damage in replicating cells and this can result in apoptosis or cancer.]]

[[DNA repair|Repair of DNA damages]] and [[apoptosis]] are two enzymatic processes essential for maintaining [[genome]] integrity in humans.  Cells that are deficient in DNA repair tend to accumulate [[DNA damage (naturally occurring)|DNA damages]], and when such cells are also defective in apoptosis they tend to survive even with excess DNA damage.<ref name="Bernstein2002">{{Cite journal |pmid=12052432 |date=2002 |last1=Bernstein |first1=C. |last2=Bernstein |first2=H. |last3=Payne |first3=C. M. |last4=Garewal |first4=H. |title=DNA repair/Pro-apoptotic dual-role proteins in five major DNA repair pathways: Fail-safe protection against carcinogenesis |journal=Mutation Research |volume=511 |issue=2 |pages=145–178 |doi=10.1016/s1383-5742(02)00009-1 }}</ref>  Replication of DNA in such cells leads to [[mutation]]s and these mutations may cause cancer (see Figure).  Several enzymatic pathways have evolved for repairing different kinds of DNA damage, and it has been found that in five well studied DNA repair pathways particular enzymes have a dual role, where one role is to participate in repair of a specific class of damages and the second role is to induce apoptosis if the level of such DNA damage is beyond the cell's repair capability.<ref name = Bernstein2002/>  These dual role proteins tend to protect against development of cancer.  Proteins that function in such a dual role for each repair process are: (1) [[DNA mismatch repair]], [[MSH2]], [[MSH6]], [[MLH1]] and [[PMS2]]; (2) [[base excision repair]], [[APEX1]] (REF1/APE), [[PARP1|poly(ADP-ribose) polymerase]] (PARP); (3) [[nucleotide excision repair]], [[XPB]], XPD ([[ERCC2]]), [[p53]], p33([[ING1]]b); (4) [[non-homologous end joining]], the catalytic subunit of [[DNA-PKcs|DNA-PK]]; (5) [[homologous recombination]]al repair, [[BRCA1]], [[ATM serine/threonine kinase|ATM]], [[ataxia telangiectasia and Rad3 related|ATR]], [[Werner syndrome helicase|WRN]], [[Bloom syndrome protein|BLM]], [[KAT5|Tip60]], [[p53]].

==Programmed death of entire organisms==
{{main|Phenoptosis}}

== Clinical significance ==

=== ABL ===

The BCR-ABL oncogene has been found to be involved in the development of [[cancer]] in humans.<ref name="srivastava2007">{{cite book|last=Srivastava|first=Rakesh|title=Apoptosis, Cell Signaling, and Human Diseases|year=2007|publisher=Humana Press}}</ref>

=== c-Myc ===

[[c-Myc]] is involved in the regulation of apoptosis via its role in downregulating the [[Bcl-2]] gene. Its role the disordered growth of tissue.<ref name="srivastava2007"/>

=== Metastasis ===

A [[molecular]] characteristic of metastatic cells is their altered expression of several apoptotic genes.<ref name="srivastava2007"/>

==See also==
{{div col|colwidth=20em}}
* [[Anoikis]]
* [[Apoptosis-inducing factor]]
* [[Apoptosis]] versus [[Pseudoapoptosis]]
* [[Apoptosome]]
* [[Apoptotic DNA fragmentation]]
* [[Autolysis (biology)]]
* [[Autophagy]]
* [[Autoschizis]]
* [[Bcl-2]]
* [[BH3 interacting domain death agonist]] (BID)
* [[Calpain]]s
* [[Caspases]]
* [[Cell damage]]
* [[Cornification]]
* [[Cytochrome c]]
* [[Cytotoxicity]]
* [[Diablo homolog]]
* [[Entosis]]
* [[Excitotoxicity]]
* [[Ferroptosis]]
* [[Inflammasome]]
* [[Mitochondrial permeability transition pore]]
* [[Mitotic catastrophe]]
* [[Necrobiology]]
* [[Necroptosis]]
* [[Necrosis]]
* [[p53 upregulated modulator of apoptosis]] (PUMA)
* [[Paraptosis]]
* [[Parthanatos]]
* [[Pyroptosis]]
* [[RIP kinase]]s
* [[Wallerian degeneration]]
{{Div col end}}

== Notes and references ==
* Srivastava, R. E. in Molecular Mechanisms    (Humana Press, 2007).
* Kierszenbaum, A. L. & Tres, L. L. (ed Madelene Hyde) (ELSEVIER SAUNDERS, Philadelphia, 2012).

{{Reflist|2}}

==External links==
* [http://www.caspases.org Apoptosis and Cell Death Labs]
* [http://www.celldeath-apoptosis.org International Cell Death Society]
* [http://bcl2db.ibcp.fr The Bcl-2 Family Database] {{Webarchive|url=https://web.archive.org/web/20090221095434/http://bcl2db.ibcp.fr/ |date=2009-02-21 }}

{{senescence}}
{{Fas apoptosis signaling pathway}}
{{embryology}}

[[Category:Programmed cell death| ]]
[[Category:Mitochondria]]
[[Category:Cellular senescence]]
[[Category:Apoptosis]]