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}} {{cs1 config|name-list-style=vanc|display-authors=6}}

'''Programmed cell death''' ('''PCD'''), sometimes referred to as '''cell suicide or cellular suicide,'''<ref>{{cite journal | vauthors = Raff M | title = Cell suicide for beginners | journal = Nature | volume = 396 | issue = 6707 | pages = 119–122 | date = November 1998 | pmid = 9823889 | doi = 10.1038/24055 | s2cid = 4341684 | doi-access = free | bibcode = 1998Natur.396..119R }}</ref><ref name="Albert's">{{cite web | vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P | title = Programmed Cell Death (Apoptosis) | date = 2002 | 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 }}</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 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 | title = Bacterial programmed cell death and multicellular behavior in bacteria | journal = PLOS Genetics | volume = 2 | issue = 10 | pages = e135 | date = October 2006 | pmid = 17069462 | pmc = 1626106 | doi = 10.1371/journal.pgen.0020135 | doi-access = free }} </ref><ref>{{cite book | vauthors = Green D | title = Means To An End | location = New York | year = 2011 | publisher = Cold Spring Harbor Laboratory Press | 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 lifecycle. For example, the 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="Kierszenbaum_2012">{{cite book | vauthors = Kierszenbaum A | title = Histology and Cell Biology - An Introduction to Pathology | location = Philadelphia | year = 2012 | publisher = ELSEVIER SAUNDERS }}</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="Kierszenbaum_2012" /> but in the 2000s, a form of programmed necrosis, called necroptosis,<ref>{{cite journal | vauthors = Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J | title = Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury | journal = Nature Chemical Biology | volume = 1 | issue = 2 | pages = 112–119 | date = July 2005 | pmid = 16408008 | doi = 10.1038/nchembio711 | bibcode = 2005NatCB...1..112D | 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 | title = Regulated necrosis: the expanding network of non-apoptotic cell death pathways | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 2 | pages = 135–147 | date = February 2014 | pmid = 24452471 | doi = 10.1038/nrm3737 | bibcode = 2014NRMCB..15..135B | s2cid = 13919892 }}</ref>

==History== The concept of "programmed cell-death" was used by Lockshin & Williams<ref name="Lockshin_1964">{{cite journal | vauthors = Lockshin RA, Williams CM | 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 | year = 1964 | 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 | vauthors = Durand and Ramsey PM | title = The nature of programmed cell death | journal = Biological Theory | volume = 14 | pages = 30–41 | date = 2019 | 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}}<ref>{{Cite journal |last1=Chen |first1=Yao |last2=Li |first2=Xiaohua |last3=Yang |first3=Minfeng |last4=Liu |first4=Song-Bai |date=2024-05-10 |title=Research progress on morphology and mechanism of programmed cell death |url=https://www.nature.com/articles/s41419-024-06712-8 |journal=Cell Death & Disease |language=en |volume=15 |issue=5 |pages=327 |doi=10.1038/s41419-024-06712-8 |issn=2041-4889|pmc=11087523 }}</ref>

The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations 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="Vaux_1988">{{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 = 440–442 | date = September 1988 | pmid = 3262202 | doi = 10.1038/335440a0 | s2cid = 23593952 | bibcode = 1988Natur.335..440V }}</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 | year = 2002 | url = http://nobelprize.org/nobel_prizes/medicine/laureates/2002/index.html | publisher = The Nobel Foundation | 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. (''Cytoplasmic'': characterized by the formation of large vacuoles that eat away organelles in a specific sequence prior to the destruction of the nucleus.)<ref> {{cite journal | vauthors = Schwartz LM, Smith SW, Jones ME, Osborne BA | title = Do all programmed cell deaths occur via apoptosis? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 3 | pages = 980–984 | date = February 1993 | pmid = 8430112 | pmc = 45794 | doi = 10.1073/pnas.90.3.980 | doi-access = free | bibcode = 1993PNAS...90..980S }};and, for a more recent view, see {{cite journal | vauthors = Bursch W, Ellinger A, Gerner C, Fröhwein U, Schulte-Hermann R | 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 | year = 2000 | pmid = 11193023 | doi = 10.1111/j.1749-6632.2000.tb05594.x | s2cid = 27315958 | bibcode = 2000NYASA.926....1B }}</ref>

=== Apoptosis ===

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.<ref>{{cite book | vauthors = Green D | title = Means To An End | location = New York | year = 2011 | publisher = Cold Spring Harbor Laboratory Press | isbn = 978-0-87969-888-1 | url = http://celldeathbook.wordpress.com/ }}</ref> Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and 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 | vauthors = Bowen ID | title = Apoptosis or programmed cell death? | journal = Cell Biology International | volume = 17 | issue = 4 | pages = 365–380 | date = April 1993 | pmid = 8318948 | doi = 10.1006/cbir.1993.1075 | url = http://www.cellbiolint.org/cbi/017/cbi0170365.htm#CitedBy | access-date = 2012-10-03 | url-status = dead | s2cid = 31016389 | url-access = subscription | archive-url = https://web.archive.org/web/20140312224446/http://www.cellbiolint.org/cbi/017/cbi0170365.htm#CitedBy | archive-date = 2014-03-12 }}</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.<ref>{{Cite journal |date=2024-11-06 |title=Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications |journal=Cells |volume=13 |issue=22 |pages=1838 |doi=10.3390/cells13221838 |doi-access=free |issn=2073-4409 |pmc=11592877 |pmid=39594587| vauthors = Mustafa M, Ahmad R, Tantry IQ, Ahmad W, Siddiqui S, Alam M, Abbas K, Moinuddin, Hassan MI, Habib S, Islam S }}</ref>

===== 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 ligand 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 | Intrinsic and extrinsic pathway | USMLE step 1 | Pathology | date = 8 January 2023 | website = YouTube | 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 | date = 30 March 2019 | website = YouTube | url = https://www.youtube.com/watch?v=jRZHDhHf3tA }}</ref>

=== Autophagy ===

Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomal-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles.<ref name="Kierszenbaum_2012" />

Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, 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, 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 ATG genes 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.<ref name=":0">{{Cite web |title=Autophagy |url=https://my.clevelandclinic.org/health/articles/24058-autophagy |website=Cleveland Clinic}}</ref>

Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.<ref name=":0" />

===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 | title = Caspase-independent cell death | journal = Nature Medicine | volume = 11 | issue = 7 | pages = 725–730 | date = July 2005 | pmid = 16015365 | doi = 10.1038/nm1263 | bibcode = 2005NatMe..11..725K | 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.<ref name=":1">{{Cite journal |last=Tait |first=Stephen W. G. |last2=Ichim |first2=Gabriel |last3=Green |first3=Douglas R. |date=2014-05-15 |title=Die another way--non-apoptotic mechanisms of cell death |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC4021468/ |journal=Journal of Cell Science |volume=127 |issue=Pt 10 |pages=2135–2144 |doi=10.1242/jcs.093575 |issn=1477-9137 |pmc=4021468 |pmid=24833670}}</ref>

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 | vauthors = Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR | title = Ferroptosis: an iron-dependent form of nonapoptotic cell death | journal = Cell | volume = 149 | issue = 5 | pages = 1060–1072 | date = May 2012 | pmid = 22632970 | pmc = 3367386 | doi = 10.1016/j.cell.2012.03.042 }}</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="Bizik_2004">{{cite journal | vauthors = Bizik J, Kankuri E, Ristimäki A, Taïeb A, Vapaatalo H, Lubitz W, Vaheri A | title = Cell-cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression | journal = Cell Death and Differentiation | volume = 11 | issue = 2 | pages = 183–195 | date = February 2004 | pmid = 14555963 | doi = 10.1038/sj.cdd.4401317 | doi-access = free }}</ref>

Eryptosis is a form of suicidal erythrocyte death.<ref>{{cite journal | vauthors = Lang F, Lang KS, Lang PA, Huber SM, Wieder T | title = Mechanisms and significance of eryptosis | journal = Antioxidants & Redox Signaling | volume = 8 | issue = 7–8 | pages = 1183–1192 | year = 2006 | pmid = 16910766 | doi = 10.1089/ars.2006.8.1183 }}</ref>

Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.<ref>{{cite journal | vauthors = Formigli L, Papucci L, Tani A, Schiavone N, Tempestini A, Orlandini GE, Capaccioli S, Orlandini SZ | 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 | date = January 2000 | pmid = 10567915 | doi = 10.1002/(sici)1097-4652(200001)182:1<41::aid-jcp5>3.0.co;2-7 | s2cid = 20064300 }}</ref>

NETosis is the process of cell-death generated by neutrophils, resulting in NETs.<ref>{{cite journal | vauthors = Fadini GP, Menegazzo L, Scattolini V, Gintoli M, Albiero M, Avogaro A | title = A perspective on NETosis in diabetes and cardiometabolic disorders | journal = Nutrition, Metabolism, and Cardiovascular Diseases | volume = 26 | issue = 1 | pages = 1–8 | date = January 2016 | pmid = 26719220 | doi = 10.1016/j.numecd.2015.11.008 }}</ref>

Paraptosis is another type of nonapoptotic cell death that is mediated by MAPK through the activation of IGF-1. It's characterized by the intracellular formation of vacuoles and swelling of mitochondria.<ref name="Ross_2016">{{Cite book | vauthors = Ross M | title = Histology: A Text and Atlas | pages = 94 | year = 2016 | edition = 7th | 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="Ross_2016" />

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.<ref name=":1" />

== Atrophic factors ==

An atrophic factor is a force that causes a cell to 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>{{cite book | vauthors = Phelps JR | chapter-url = http://www.psycheducation.org/mechanism/10AllPlayers.htm | chapter = Chapter 10: All the Players on One Stage | title = From Stress to Genes, from Mind to Molecules | archive-url = https://web.archive.org/web/20130528172823/http://www.psycheducation.org/mechanism/10AllPlayers.htm | archive-date=2013-05-28 | publisher = 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== 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_2010">{{cite journal | vauthors = Tau GZ, Peterson BS | title = Normal development of brain circuits | journal = Neuropsychopharmacology | volume = 35 | issue = 1 | pages = 147–168 | date = January 2010 | pmid = 19794405 | pmc = 3055433 | doi = 10.1038/npp.2009.115 }}</ref> During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).<ref name="Dekkers_2013">{{cite journal | vauthors = Dekkers MP, Nikoletopoulou V, Barde YA | title = Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity | journal = The Journal of Cell Biology | volume = 203 | issue = 3 | pages = 385–393 | date = November 2013 | pmid = 24217616 | pmc = 3824005 | doi = 10.1083/jcb.201306136 }}</ref> PCD in the nervous system was first recognized in 1896 by John Beard.<ref name="Oppenheim 1981">{{cite book | vauthors = Oppenheim R | title = Neuronal cell death and some related regressive phenomena during neurogenesis: a selective historical review and progress report | location = In Studies in Developmental Neurobiology: Essays in Honor of Viktor Hamburger | pages = 74–133 | year = 1981 | publisher = Oxford University Press }}</ref> Since then several theories were proposed to understand its biological significance during neural development.<ref name="Buss_2006">{{cite journal | vauthors = Buss RR, Sun W, Oppenheim RW | title = Adaptive roles of programmed cell death during nervous system development | journal = Annual Review of Neuroscience | volume = 29 | pages = 1–35 | year = 2006 | pmid = 16776578 | doi = 10.1146/annurev.neuro.29.051605.112800 }}</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_2010" /> 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 | vauthors = de la Rosa EJ, de Pablo F | title = Cell death in early neural development: beyond the neurotrophic theory | journal = Trends in Neurosciences | volume = 23 | issue = 10 | pages = 454–458 | date = October 2000 | pmid = 11006461 | doi = 10.1016/s0166-2236(00)01628-3 | 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_2006" /> At gestational weeks 19–23, PCD is observed in post-mitotic cells.<ref name="Lossiand Merighi">{{cite journal | vauthors = Lossi L, Merighi A | title = In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS | journal = Progress in Neurobiology | volume = 69 | issue = 5 | pages = 287–312 | date = April 2003 | pmid = 12787572 | doi = 10.1016/s0301-0082(03)00051-0 | 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_2006" /> 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_1989">{{cite journal | vauthors = Finlay BL, Pallas SL | title = Control of cell number in the developing mammalian visual system | journal = Progress in Neurobiology | volume = 32 | issue = 3 | pages = 207–234 | year = 1989 | pmid = 2652194 | doi = 10.1016/0301-0082(89)90017-8 | s2cid = 2788103 | doi-access = free }}</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_2006" />

===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 | vauthors = Yamaguchi Y, Miura M | title = Programmed cell death in neurodevelopment | journal = Developmental Cell | volume = 32 | issue = 4 | pages = 478–490 | date = February 2015 | pmid = 25710534 | doi = 10.1016/j.devcel.2015.01.019 | 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 | vauthors = Rubenstein J, Rakic P | chapter = Regulation of Neuronal Survival by Neurotrophins in the Developing Peripheral Nervous System | 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 }}</ref>

The underlying idea that target cells secrete attractive or inducing factors and that their growth cones have a chemotactic sensitivity was first put forth by Santiago Ramon y Cajal in 1892.<ref name="Constantino_2002">{{cite book | vauthors = Constantino S | chapter = Chapter 2 the chemotactic hypothesis of Cajal: A century behind | title = Changing Views of Cajal's Neuron | volume = 136 | pages = 11–20 | year = 2002 | pmid = 12143376 | doi = 10.1016/s0079-6123(02)36004-7 | series = Progress in Brain Research | isbn = 978-0-444-50815-7 }}</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="Constantino_2002" /> 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 | vauthors = Oppenheim RW | title = The neurotrophic theory and naturally occurring motoneuron death | journal = Trends in Neurosciences | volume = 12 | issue = 7 | pages = 252–255 | date = July 1989 | pmid = 2475935 | doi = 10.1016/0166-2236(89)90021-0 | s2cid = 3957751 }}</ref><ref name="Death in developing">{{cite journal | vauthors = Dekkers MP, Nikoletopoulou V, Barde YA | title = Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity | journal = The Journal of Cell Biology | volume = 203 | issue = 3 | pages = 385–393 | date = November 2013 | pmid = 24217616 | pmc = 3824005 | doi = 10.1083/jcb.201306136 }}</ref> Experiments that further supported this theory led to the identification of the first neurotrophic factor, nerve growth factor (NGF).<ref name="Cowan_2001">{{cite journal | vauthors = Cowan WM | title = Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor | journal = Annual Review of Neuroscience | volume = 24 | pages = 551–600 | year = 2001 | pmid = 11283321 | doi = 10.1146/annurev.neuro.24.1.551 | s2cid = 6747529 }}</ref>

===Peripheral versus central nervous system=== 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_1987">{{cite journal | vauthors = Weltman 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 and Regional Allergy Proceedings | volume = 8 | issue = 1 | pages = 47–48 | date = February 8, 1987 | pmid = 3302667 | doi = 10.2500/108854187779045385 }}</ref><ref name="Dekkers_2013a">{{cite journal | vauthors = Dekkers MP, Barde YA | title = Developmental biology. Programmed cell death in neuronal development | journal = Science | volume = 340 | issue = 6128 | pages = 39–41 | date = April 2013 | pmid = 23559240 | doi = 10.1126/science.1236152 | s2cid = 206548254 | bibcode = 2013Sci...340...39D }}</ref> Expression of neurotrophin receptors, TrkA and TrkC, is sufficient to induce apoptosis in the absence of their ligands.<ref name="Dekkers_2013" /> 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.<ref name=":2">{{Cite web |title=peripheral nervous system |url=https://my.clevelandclinic.org/health/body/23123-peripheral-nervous-system-pns |website=Cleveland Clinic}}</ref>

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="Dekkers_2013a" /> Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured in vitro.<ref name="Southwell_2012">{{cite journal | vauthors = Southwell DG, Paredes MF, Galvao RP, Jones DL, Froemke RC, Sebe JY, Alfaro-Cervello C, Tang Y, Garcia-Verdugo JM, Rubenstein JL, Baraban SC, Alvarez-Buylla A | title = Intrinsically determined cell death of developing cortical interneurons | journal = Nature | volume = 491 | issue = 7422 | pages = 109–113 | date = November 2012 | pmid = 23041929 | pmc = 3726009 | doi = 10.1038/nature11523 | 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 Bax (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice.<ref name="Southwell_2012" /> 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.<ref name=":2" />

===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_2006" /> 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_1998">{{cite journal | vauthors = Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA | title = Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9 | journal = Cell | volume = 94 | issue = 3 | pages = 325–337 | date = August 1998 | pmid = 9708735 | doi = 10.1016/s0092-8674(00)81476-2 | s2cid = 8417446 | doi-access = free }}</ref><ref name="Kuida decreased">{{cite journal | vauthors = Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA | title = Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice | journal = Nature | volume = 384 | issue = 6607 | pages = 368–372 | date = November 1996 | pmid = 8934524 | doi = 10.1038/384368a0 | s2cid = 4353931 | bibcode = 1996Natur.384..368K }}</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 | vauthors = Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY, Rakic P | title = Programmed cell death of developing mammalian neurons after genetic deletion of caspases | journal = The Journal of Neuroscience | volume = 21 | issue = 13 | pages = 4752–4760 | date = July 2001 | pmid = 11425902 | pmc = 6762357 | doi = 10.1523/JNEUROSCI.21-13-04752.2001 | 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_1998">{{cite journal | vauthors = Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P | title = Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development | journal = Cell | volume = 94 | issue = 6 | pages = 727–737 | date = September 1998 | pmid = 9753320 | doi = 10.1016/s0092-8674(00)81732-8 | doi-access = free }}</ref><ref name="Hao_2005">{{cite journal | vauthors = Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, Okada H, Calzascia T, Jang Y, You-Ten A, Yeh WC, Ohashi P, Wang X, Mak TW | title = Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis | journal = Cell | volume = 121 | issue = 4 | pages = 579–591 | date = May 2005 | pmid = 15907471 | doi = 10.1016/j.cell.2005.03.016 | s2cid = 4921039 | doi-access = free | bibcode = 2005Cell..121..579H }}</ref><ref name="Yoshida_1998">{{cite journal | vauthors = Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW | title = Apaf1 is required for mitochondrial pathways of apoptosis and brain development | journal = Cell | volume = 94 | issue = 6 | pages = 739–750 | date = September 1998 | pmid = 9753321 | doi = 10.1016/s0092-8674(00)81733-x | 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_1996">{{cite journal | vauthors = Bonfanti L, Strettoi E, Chierzi S, Cenni MC, Liu XH, Maffei L, Rabacchi SA | title = Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2 | journal = The Journal of Neuroscience | volume = 16 | issue = 13 | pages = 4186–4194 | date = July 1996 | pmid = 8753880 | pmc = 6578989 | doi = 10.1523/JNEUROSCI.16-13-04186.1996 | doi-access = free }}</ref><ref name="Martinou_1994">{{cite journal | vauthors = Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C | title = Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia | journal = Neuron | volume = 13 | issue = 4 | pages = 1017–1030 | date = October 1994 | pmid = 7946326 | doi = 10.1016/0896-6273(94)90266-6 | s2cid = 25546670 }}</ref><ref name="Zanjani_1996">{{cite journal | vauthors = Zanjani HS, Vogel MW, Delhaye-Bouchaud N, Martinou JC, Mariani J | title = Increased cerebellar Purkinje cell numbers in mice overexpressing a human bcl-2 transgene | journal = The Journal of Comparative Neurology | volume = 374 | issue = 3 | pages = 332–341 | date = October 1996 | pmid = 8906502 | doi = 10.1002/(sici)1096-9861(19961021)374:3<332::aid-cne2>3.0.co;2-2 | s2cid = 32460867 }}</ref><ref name="Zup_2003">{{cite journal | vauthors = Zup SL, Carrier H, Waters EM, Tabor A, Bengston L, Rosen GJ, Simerly RB, Forger NG | title = Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord | journal = The Journal of Neuroscience | volume = 23 | issue = 6 | pages = 2357–2362 | date = March 2003 | pmid = 12657695 | pmc = 6742046 | doi = 10.1523/JNEUROSCI.23-06-02357.2003 | doi-access = free }}</ref><ref name="Fan_2001">{{cite journal | vauthors = Fan H, Favero M, Vogel MW | title = Elimination of Bax expression in mice increases cerebellar purkinje cell numbers but not the number of granule cells | journal = The Journal of Comparative Neurology | volume = 436 | issue = 1 | pages = 82–91 | date = July 2001 | pmid = 11413548 | doi = 10.1002/cne.1055.abs }}</ref><ref name="Mosinger_1998">{{cite journal | vauthors = Mosinger O | title = Suppression of developmental retinal cell death but not of photoreceptor degeneration in Bax-deficient mice | journal = Investigative Ophthalmology & Visual Science | volume = 39 | pages = 1713–1720 | year = 1998 | pmid = 9699561 }}</ref><ref name="White_1998">{{cite journal | vauthors = White FA, Keller-Peck CR, Knudson CM, Korsmeyer SJ, Snider WD | title = Widespread elimination of naturally occurring neuronal death in Bax-deficient mice | journal = The Journal of Neuroscience | volume = 18 | issue = 4 | pages = 1428–1439 | date = February 1998 | pmid = 9454852 | pmc = 6792725 | doi = 10.1523/JNEUROSCI.18-04-01428.1998 | 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_1999">{{cite journal | vauthors = Gianfranceschi L, Fiorentini A, Maffei L | title = Behavioural visual acuity of wild type and bcl2 transgenic mouse | journal = Vision Research | volume = 39 | issue = 3 | pages = 569–574 | date = February 1999 | pmid = 10341985 | doi = 10.1016/s0042-6989(98)00169-2 | s2cid = 5544203 | doi-access = free }}</ref><ref name="RondiReig_2002">{{cite journal | vauthors = Rondi-Reig L, Mariani J | 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 | volume = 57 | issue = 1 | pages = 85–91 | date = January 2002 | pmid = 11827740 | doi = 10.1016/s0361-9230(01)00639-6 | s2cid = 35145189 }}</ref><ref name="Rondi Transgenic Mice">{{cite journal | vauthors = Rondi-Reig L, Lemaigre-Dubreuil Y, Montécot C, Müller D, Martinou JC, Caston J, Mariani J | title = Transgenic mice with neuronal overexpression of bcl-2 gene present navigation disabilities in a water task | journal = Neuroscience | volume = 104 | issue = 1 | pages = 207–215 | year = 2001 | pmid = 11311543 | doi = 10.1016/s0306-4522(01)00050-1 | 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_2006" />

===Invertebrates and vertebrates=== 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 | vauthors = Buss RR, Sun W, Oppenheim RW | title = Adaptive roles of programmed cell death during nervous system development | journal = Annual Review of Neuroscience | volume = 29 | issue = 1 | pages = 1–35 | date = 2006-07-21 | pmid = 16776578 | doi = 10.1146/annurev.neuro.29.051605.112800 }}</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_1980">{{cite journal | vauthors = Sulston JE, Albertson DG, Thomson JN | title = The Caenorhabditis elegans male: postembryonic development of nongonadal structures | journal = Developmental Biology | volume = 78 | issue = 2 | pages = 542–576 | date = August 1980 | pmid = 7409314 | doi = 10.1016/0012-1606(80)90352-8 }}</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="Sulston_1983">{{cite journal | vauthors = Sulston JE, Schierenberg E, White JG, Thomson JN | title = The embryonic cell lineage of the nematode Caenorhabditis elegans | journal = Developmental Biology | volume = 100 | issue = 1 | pages = 64–119 | date = November 1983 | pmid = 6684600 | doi = 10.1016/0012-1606(83)90201-4 }}</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_1985">{{cite journal | vauthors = Doe CQ, Goodman CS | title = Early events in insect neurogenesis. I. Development and segmental differences in the pattern of neuronal precursor cells | journal = Developmental Biology | volume = 111 | issue = 1 | pages = 193–205 | date = September 1985 | pmid = 4029506 | doi = 10.1016/0012-1606(85)90445-2 }}</ref> Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.<ref name="Giebultowicz_1984">{{cite journal | vauthors = Giebultowicz JM, Truman JW | title = Sexual differentiation in the terminal ganglion of the moth Manduca sexta: role of sex-specific neuronal death | journal = The Journal of Comparative Neurology | volume = 226 | issue = 1 | pages = 87–95 | date = June 1984 | pmid = 6736297 | doi = 10.1002/cne.902260107 | 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_2006" /> 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_1998">{{cite journal | vauthors = Cook B, Portera-Cailliau C, Adler R | title = Developmental neuronal death is not a universal phenomenon among cell types in the chick embryo retina | journal = The Journal of Comparative Neurology | volume = 396 | issue = 1 | pages = 12–19 | date = June 1998 | pmid = 9623884 | doi = 10.1002/(sici)1096-9861(19980622)396:1<12::aid-cne2>3.0.co;2-l | s2cid = 25569721 }}</ref> Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.<ref name="Buss_2006" />

==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 | title = Programmed cell death in plants resembles apoptosis of animals | journal = Biotecnología Aplicada | volume = 23 | pages = 1–10 | year = 2006 | url = http://elfosscientiae.cigb.edu.cu/PDFs/BA/2006/23/1/BA002301RV001-010.pdf | 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",<ref> {{cite journal | vauthors = Bonke M, Thitamadee S, Mähönen AP, Hauser MT, Helariutta Y | title = APL regulates vascular tissue identity in Arabidopsis | journal = Nature | volume = 426 | issue = 6963 | pages = 181–186 | date = November 2003 | pmid = 14614507 | doi = 10.1038/nature02100 | s2cid = 12672242 | bibcode = 2003Natur.426..181B }}</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 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 kingdoms.<ref> {{cite journal | vauthors = Solomon M, Belenghi B, Delledonne M, Menachem E, Levine A | 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 = 431–444 | date = March 1999 | pmid = 10072402 | pmc = 144188 | doi = 10.2307/3870871 | bibcode = 1999PlanC..11..431S | jstor = 3870871 }} 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 nuclear degradation triggered by the collapse of the vacuole in tracheary elements of the xylem.<ref> {{cite journal | vauthors = Ito J, Fukuda H | 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 = 3201–3211 | date = December 2002 | pmid = 12468737 | pmc = 151212 | doi = 10.1105/tpc.006411 | bibcode = 2002PlanC..14.3201I }}</ref>

Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant PCD as in other eukaryotic cells.<ref> {{cite journal | vauthors = Balk J, Leaver CJ | 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 = 1803–1818 | date = August 2001 | 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 ('''SI''') as an important means to prevent self-fertilization. Research on the corn poppy (''Papaver rhoeas'') has revealed that proteins 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 E. Franklin-Tong, also found that the response involves rapid inhibition of pollen-tube growth, followed by PCD.<ref> {{cite journal | vauthors = Thomas SG, Franklin-Tong VE | title = Self-incompatibility triggers programmed cell death in Papaver pollen | journal = Nature | volume = 429 | issue = 6989 | pages = 305–309 | date = May 2004 | pmid = 15152254 | doi = 10.1038/nature02540 | s2cid = 4376774 | bibcode = 2004Natur.429..305T }}</ref>

==In slime molds== The social slime mold ''Dictyostelium discoideum'' has the peculiarity of either adopting a predatory amoeba-like behavior in its unicellular form or coalescing into a mobile slug-like form when dispersing the spores that will give birth to the next generation.<ref> {{cite journal | vauthors = Crespi B, Springer S | title = Ecology. Social slime molds meet their match | journal = Science | volume = 299 | issue = 5603 | pages = 56–57 | date = January 2003 | 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 DNA fragmentation.<ref> {{cite journal | vauthors = Levraud JP, Adam M, Luciani MF, de Chastellier C, Blanton RL, Golstein P | title = Dictyostelium cell death: early emergence and demise of highly polarized paddle cells | journal = The Journal of Cell Biology | volume = 160 | issue = 7 | pages = 1105–1114 | date = March 2003 | 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 eukaryotic ancestors about a billion years before the present. It seems that they emerged after the ancestors of green plants and the ancestors of fungi and animals had differentiated. But, in addition to their place in the evolutionary 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 | title = Developmental cell death in dictyostelium does not require paracaspase | journal = The Journal of Biological Chemistry | volume = 279 | issue = 12 | pages = 11489–11494 | date = March 2004 | 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 protists is possible,<ref>{{cite journal | vauthors = Deponte M | title = Programmed cell death in protists | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1783 | issue = 7 | pages = 1396–1405 | date = July 2008 | pmid = 18291111 | doi = 10.1016/j.bbamcr.2008.01.018 | doi-access = free }}</ref><ref name = "Kaczanowski_2011" /> but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.<ref>{{cite journal | vauthors = Proto WR, Coombs GH, Mottram JC | title = Cell death in parasitic protozoa: regulated or incidental? | journal = Nature Reviews. Microbiology | volume = 11 | issue = 1 | pages = 58–66 | date = January 2013 | pmid = 23202528 | doi = 10.1038/nrmicro2929 | url = http://www.gla.ac.uk/media/media_248886_en.pdf | access-date = 2014-11-14 | url-status = dead | s2cid = 1633550 | archive-url = https://web.archive.org/web/20160303235943/http://www.gla.ac.uk/media/media_248886_en.pdf | archive-date = 2016-03-03 }}</ref><ref name = "Kaczanowski_2011">{{cite journal | vauthors = Kaczanowski S, Sajid M, Reece SE | title = Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites | journal = Parasites & Vectors | volume = 4 | article-number = 44 | date = March 2011 | pmid = 21439063 | pmc = 3077326 | doi = 10.1186/1756-3305-4-44 | doi-access = free }}</ref>

Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts ("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 | vauthors = de Duve C | title = The birth of complex cells | journal = Scientific American | volume = 274 | issue = 4 | pages = 50–57 | date = April 1996 | pmid = 8907651 | doi = 10.1038/scientificamerican0496-50 | author-link = Christian de Duve | 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 genes and replication apparatus.

This evolutionary step would have been risky for the primitive eukaryotic cells, which began to engulf the energy-producing bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic hosts. This process is still evident today, between human white 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 prokaryotes to succeed, with the consequence known as infection by its resulting damage.{{cn|date=November 2024}}

One of these rare evolutionary events, about 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 | title = Ancient invasions: from endosymbionts to organelles | journal = Science | volume = 304 | issue = 5668 | pages = 253–257 | date = April 2004 | pmid = 15073369 | doi = 10.1126/science.1094884 | s2cid = 19424594 | bibcode = 2004Sci...304..253D }}</ref>

Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide.<ref>{{cite journal | vauthors = Chiarugi A, Moskowitz MA | title = Cell biology. PARP-1--a perpetrator of apoptotic cell death? | journal = Science | volume = 297 | issue = 5579 | pages = 200–201 | date = July 2002 | 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 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 damage), mitochondria release caspase activators that trigger the cell-death-inducing biochemical cascade. As such, the cell suicide mechanism is now crucial to all of our lives.

==DNA damage and apoptosis==

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

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 damages, and when such cells are also defective in apoptosis they tend to survive even with excess DNA damage.<ref name="Bernstein_2002">{{cite journal | vauthors = Bernstein C, Bernstein H, Payne CM, Garewal 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 | date = June 2002 | pmid = 12052432 | doi = 10.1016/s1383-5742(02)00009-1 | bibcode = 2002MRRMR.511..145B }}</ref> Replication of DNA in such cells leads to mutations 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="Bernstein_2002" /> 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), poly(ADP-ribose) polymerase (PARP); (3) nucleotide excision repair, XPB, XPD (ERCC2), p53, p33(ING1b); (4) non-homologous end joining, the catalytic subunit of DNA-PK; (5) homologous recombinational repair, BRCA1, ATM, ATR, WRN, BLM, 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 | vauthors = Srivastava R | 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" />

== References == {{Reflist}}

Category:Programmed cell death Category:Mitochondria Category:Cellular senescence Category:Apoptosis