Editing Apoptosis (section)

==Activation mechanisms==
[[File:Apoptosis.png|right]]
[[File:Control Of The Apoptosis Mecanisms.pdf|thumb|alt=Control Of The Apoptotic Mechanisms|Control of the apoptotic mechanisms]]

The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably leads to the death of the cell.{{sfn|Alberts|p=1029}}<ref name="pmid14499155"/> The two best-understood activation mechanisms are the intrinsic pathway (also called the [[mitochondrial]] pathway) and the extrinsic pathway.{{sfn|Alberts|p=1023}} The ''intrinsic pathway'' is activated by intracellular signals generated when cells are stressed and depends on the release of proteins from the intermembrane space of mitochondria.{{sfn|Alberts|p=1032}} The ''extrinsic pathway'' is activated by extracellular ligands binding to cell-surface death receptors, which leads to the formation of the [[death-inducing signaling complex]] (DISC).{{sfn|Alberts|p=1024}}

A cell initiates intracellular apoptotic signaling in response to a stress,<ref>{{cite journal | last1=Nirmala | first1=J. Grace | last2=Lopus | first2=Manu | title=Cell death mechanisms in eukaryotes | journal=Cell Biology and Toxicology | volume=36 | issue=2 | date=2020 | issn=1573-6822 | pmid=31820165 | doi=10.1007/s10565-019-09496-2 | pages=145–164| s2cid=208869679 }}</ref> which may bring about cell death. The binding of nuclear receptors by [[glucocorticoid]]s,<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease|  vauthors = Cotran RS, Kumar C | publisher=W.B Saunders Company| location=Philadelphia| isbn=978-0-7216-7335-6 | year=1998 }}</ref> heat,<ref name="robspath"/> radiation,<ref name="robspath"/> nutrient deprivation,<ref name="robspath"/> viral infection,<ref name="robspath"/> [[Hypoxia (medical)|hypoxia]],<ref name="robspath"/> increased intracellular concentration of free fatty acids<ref>{{cite journal | vauthors = Hardy S, El-Assaad W, Przybytkowski E, Joly E, Prentki M, Langelier Y | title = Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin | journal = The Journal of Biological Chemistry | volume = 278 | issue = 34 | pages = 31861–31870 | date = August 2003 | pmid = 12805375 | doi = 10.1074/jbc.m300190200 | doi-access =  free}}</ref> and increased intracellular [[calcium]] concentration,<ref name="pmid14647298">{{cite journal | vauthors = Mattson MP, Chan SL | title = Calcium orchestrates apoptosis | journal = Nature Cell Biology | volume = 5 | issue = 12 | pages = 1041–1043 | date = December 2003 | pmid = 14647298 | doi = 10.1038/ncb1203-1041 | s2cid = 38427579 | url = https://zenodo.org/record/1233353 | access-date = 2018-05-18 | archive-date = 2019-11-21 | archive-url = https://web.archive.org/web/20191121062421/https://zenodo.org/record/1233353 | url-status = live }}</ref><ref name="pmid19898892">{{cite journal | vauthors = Uğuz AC, Naziroğlu M, Espino J, Bejarano I, González D, Rodríguez AB, Pariente JA | title = Selenium modulates oxidative stress-induced cell apoptosis in human myeloid HL-60 cells through regulation of calcium release and caspase-3 and -9 activities | journal = The Journal of Membrane Biology | volume = 232 | issue = 1–3 | pages = 15–23 | date = December 2009 | pmid = 19898892 | doi = 10.1007/s00232-009-9212-2 | s2cid = 22215706 }}</ref> for example, by damage to the membrane, can all trigger the release of intracellular apoptotic signals by a damaged cell. A number of cellular components, such as [[poly ADP ribose polymerase]], may also help regulate apoptosis.<ref name="parp1">{{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> Single cell fluctuations have been observed in experimental studies of stress induced apoptosis.<ref>{{cite journal | vauthors = Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR | title = The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant | journal = Nature Cell Biology | volume = 2 | issue = 3 | pages = 156–162 | date = March 2000 | pmid = 10707086 | doi = 10.1038/35004029 | s2cid = 2283955 }}</ref><ref>{{cite journal | vauthors = Lee JK, Lu S, Madhukar A | title = Real-Time dynamics of Ca2+, caspase-3/7, and morphological changes in retinal ganglion cell apoptosis under elevated pressure | journal = PLOS ONE | volume = 5 | issue = 10 | pages = e13437 | date = October 2010 | pmid = 20976135 | pmc = 2956638 | doi = 10.1371/journal.pone.0013437 | doi-access = free | bibcode = 2010PLoSO...513437L }}</ref>

Before the actual process of cell death is precipitated by enzymes, apoptotic signals must cause regulatory proteins to initiate the apoptosis pathway. This step allows those signals to cause cell death, or the process to be stopped, should the cell no longer need to die. Several proteins are involved, but two main methods of regulation have been identified: the targeting of [[Mitochondrion|mitochondria]] functionality,<ref>{{cite journal | vauthors = Bejarano I, Espino J, González-Flores D, Casado JG, Redondo PC, Rosado JA, Barriga C, Pariente JA, Rodríguez AB | display-authors = 6 | title = Role of Calcium Signals on Hydrogen Peroxide-Induced Apoptosis in Human Myeloid HL-60 Cells | journal = International Journal of Biomedical Science | volume = 5 | issue = 3 | pages = 246–256 | date = September 2009 | doi = 10.59566/IJBS.2009.5246 | pmid = 23675144 | pmc = 3614781 }}</ref> or directly transducing the signal via [[Signal transducing adaptor protein|adaptor proteins]] to the apoptotic mechanisms. An extrinsic pathway for initiation identified in several toxin studies is an increase in calcium concentration within a cell caused by drug activity, which also can cause apoptosis via a calcium binding protease [[calpain]].<ref>{{Cite journal |last=Moon |first=Dong-Oh |date=19 May 2023 |title=Calcium's Role in Orchestrating Cancer Apoptosis: Mitochondrial-Centric Perspective |journal=International Journal of Molecular Sciences |language=en |volume=24 |issue=10 |pages=8982 |doi=10.3390/ijms24108982 |doi-access=free |issn= |pmc= 10218825|pmid=37240331}}</ref>

===Intrinsic pathway===
The intrinsic pathway is also known as the mitochondrial pathway. [[Mitochondrion|Mitochondria]] are essential to multicellular life.  Without them, a cell ceases to [[Cellular respiration#Aerobic respiration|respire aerobically]] and quickly dies. This fact forms the basis for some apoptotic pathways.  Apoptotic proteins that target mitochondria affect them in different ways. They may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out.<ref name="robspath"/><ref>{{cite journal | vauthors = Gonzalez D, Bejarano I, Barriga C, Rodriguez AB, Pariente JA |doi=10.2174/157436210791112172|title=Oxidative Stress-Induced Caspases are Regulated in Human Myeloid HL-60 Cells by Calcium Signal|journal=Current Signal Transduction Therapy|volume=5|issue=2|pages=181–186|year=2010 }}</ref>  There is also a growing body of evidence indicating that [[nitric oxide]] is able to induce apoptosis by helping to dissipate the [[membrane potential]] of mitochondria and therefore make it more permeable.<ref name="NO">{{cite journal | vauthors = Brüne B | title = Nitric oxide: NO apoptosis or turning it ON? | journal = Cell Death and Differentiation | volume = 10 | issue = 8 | pages = 864–869 | date = August 2003 | pmid = 12867993 | doi = 10.1038/sj.cdd.4401261 | doi-access = free }}</ref> Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible action as a signal molecule of subsequent pathways that activate apoptosis.<ref>{{cite journal | vauthors = Brüne B, von Knethen A, Sandau KB | title = Nitric oxide (NO): an effector of apoptosis | journal = Cell Death and Differentiation | volume = 6 | issue = 10 | pages = 969–975 | date = October 1999 | pmid = 10556974 | doi = 10.1038/sj.cdd.4400582 | doi-access = free }}</ref>

During apoptosis, [[Cytochrome c|cytochrome ''c'']] is released from mitochondria through the actions of the proteins [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|Bak]]. The mechanism of this release is enigmatic, but appears to stem from a multitude of Bax/Bak homo- and hetero-dimers of Bax/Bak inserted into the outer membrane.<ref>{{cite journal | vauthors = Uren RT, Iyer S, Kluck RM | title = Pore formation by dimeric Bak and Bax: an unusual pore? | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 372 | issue = 1726 | pages = 20160218 | date = August 2017 | pmid = 28630157 | pmc = 5483520 | doi = 10.1098/rstb.2016.0218 }}</ref> Once cytochrome ''c'' is released it binds with Apoptotic protease activating factor – 1 (''[[Apaf-1]]'') and [[adenosine triphosphate|ATP]], which then bind to ''pro-caspase-9'' to create a protein complex known as an [[apoptosome]].  The apoptosome cleaves the pro-caspase to its active form of [[caspase-9]], which in turn cleaves and activates pro-caspase into the effector ''caspase-3''.<ref>{{Cite journal |last1=Li |first1=Peng |last2=Nijhawan |first2=Deepak |last3=Budihardjo |first3=Imawati |last4=Srinivasula |first4=Srinivasa M |last5=Ahmad |first5=Manzoor |last6=Alnemri |first6=Emad S |last7=Wang |first7=Xiaodong |date=November 1997 |title=Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade |url=https://www.cell.com/cell/fulltext/S0092-8674(00)80434-1?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S0092867400804341?showall=true |journal=Cell |language=English |volume=91 |issue=4 |pages=479–489 |doi=10.1016/S0092-8674(00)80434-1 |pmid=9390557 |issn=0092-8674 |archive-url=http://web.archive.org/web/20220414022143/https://www.cell.com/cell/fulltext/S0092-8674(00)80434-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867400804341%3Fshowall%3Dtrue |archive-date=2022-04-14}}</ref>

Mitochondria also release proteins known as SMACs (second mitochondria-derived activator of [[caspase]]s) into the cell's [[cytosol]] following the increase in permeability of the mitochondria membranes. SMAC binds to ''[[Inhibitor of apoptosis|proteins that inhibit apoptosis]]'' (IAPs) thereby deactivating them, and preventing the IAPs from arresting the process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of [[cysteine protease]]s called [[caspase]]s,<ref name="caspcontrol">{{cite journal | vauthors = Fesik SW, Shi Y | title = Structural biology. Controlling the caspases | journal = Science | volume = 294 | issue = 5546 | pages = 1477–1478 | date = November 2001 | pmid = 11711663 | doi = 10.1126/science.1062236 | s2cid = 11392850 }}</ref> which carry out the degradation of the cell. Therefore, the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability.{{citation needed|date=November 2024}}

===Extrinsic pathway===
[[File:signal transduction pathways.png|thumb|500px|right|Overview of signal transduction pathways]]
{{multiple image
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| footer            = Overview of TNF (left) and Fas (right) signalling in apoptosis, an example of direct signal transduction
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Two theories of the direct initiation of apoptotic mechanisms in mammals have been suggested: the ''TNF-induced'' ([[tumor necrosis factor]]) model and the  ''Fas-Fas [[ligand]]-mediated'' model, both involving receptors of the ''TNF receptor'' (TNFR) family<ref name="fas">{{cite journal | vauthors = Wajant H | title = The Fas signaling pathway: more than a paradigm | journal = Science | volume = 296 | issue = 5573 | pages = 1635–1636 | date = May 2002 | pmid = 12040174 | doi = 10.1126/science.1071553 | s2cid = 29449108 | bibcode = 2002Sci...296.1635W }}</ref> coupled to extrinsic signals.

==== TNF pathway ====
[[TNF-alpha]] is a [[cytokine]] produced mainly by activated [[macrophage]]s, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF-alpha: [[TNFR1]] and [[TNFR2]]. The binding of TNF-alpha to TNFR1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain ([[TRADD]]) and Fas-associated death domain protein ([[FADD]]). [[cIAP1]]/2 can inhibit TNF-α signaling by binding to [[TRAF2]]. [[CFLAR|FLIP]] inhibits the activation of caspase-8.<ref name="tnfr1">{{cite journal | vauthors = Chen G, Goeddel DV | title = TNF-R1 signaling: a beautiful pathway | journal = Science | volume = 296 | issue = 5573 | pages = 1634–1635 | date = May 2002 | pmid = 12040173 | doi = 10.1126/science.1071924 | s2cid = 25321662 | bibcode = 2002Sci...296.1634C }}</ref> Binding of this receptor can also indirectly lead to the activation of [[transcription factor]]s involved in cell survival and inflammatory responses.<ref name="tfnpathway">{{cite journal| vauthors=Goeddel, DV| title=Connection Map for Tumor Necrosis Factor Pathway| journal=[[Science Signaling|Science's STKE]]| url=http://stke.sciencemag.org/cgi/cm/CMP_7107| doi=10.1126/stke.3822007tw132| volume=2007| issue=382| pages=tw132| year=2007| s2cid=85404086| access-date=2004-01-01| archive-date=2009-07-10| archive-url=https://web.archive.org/web/20090710024231/http://stke.sciencemag.org/cgi/cm/CMP_7107| url-status=dead}}</ref> However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner.<ref name="LAPFapoptosis">{{cite journal | vauthors = Chen W, Li N, Chen T, Han Y, Li C, Wang Y, He W, Zhang L, Wan T, Cao X | display-authors = 6 | title = The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 49 | pages = 40985–40995 | date = December 2005 | pmid = 16188880 | doi = 10.1074/jbc.M502190200 | doi-access = free }}{{Retracted|doi=10.1016/j.jbc.2021.100764|http://retractionwatch.com/?s=%22Xuetao+Cao%22 ''Retraction Watch''|intentional=yes}}</ref>{{better source needed|date=October 2024}} The link between TNF-alpha and apoptosis shows why an abnormal production of TNF-alpha plays a fundamental role in several human diseases, especially in [[autoimmune disease]]s. The [[TNF receptor superfamily|TNF-alpha receptor superfamily]] also includes death receptors (DRs), such as [[Death receptor 4|DR4]] and [[Death receptor 5|DR5]]. These receptors bind to the protein [[TRAIL]] and mediate apoptosis. Apoptosis is known to be one of the primary mechanisms of targeted cancer therapy.<ref>{{cite journal | vauthors = Gerl R, Vaux DL | title = Apoptosis in the development and treatment of cancer | journal = Carcinogenesis | volume = 26 | issue = 2 | pages = 263–270 | date = February 2005 | pmid = 15375012 | doi = 10.1093/carcin/bgh283 | doi-access = free }}</ref> Luminescent iridium complex-peptide hybrids (IPHs) have recently been designed, which mimic TRAIL and bind to death receptors on cancer cells, thereby inducing their apoptosis.<ref>{{cite journal | vauthors = Masum AA, Yokoi K, Hisamatsu Y, Naito K, Shashni B, Aoki S | title = Design and synthesis of a luminescent iridium complex-peptide hybrid (IPH) that detects cancer cells and induces their apoptosis | journal = Bioorganic & Medicinal Chemistry | volume = 26 | issue = 17 | pages = 4804–4816 | date = September 2018 | pmid = 30177492 | doi = 10.1016/j.bmc.2018.08.016 | s2cid = 52149418 }}</ref>

==== Fas pathway ====
{{main|Activation-induced cell death}}

The [[fas receptor]]  (First apoptosis signal) – (also known as ''Apo-1'' or ''CD95'') is a [[transmembrane protein]] of the TNF family which binds the [[FAS ligand|Fas ligand]] (FasL).<ref name="fas"/> The interaction between Fas and FasL results in the formation of the ''death-inducing signaling complex'' (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis of the cell. In other types of cells (type II), the ''Fas''-DISC starts a feedback loop that spirals into increasing release of proapoptotic factors from mitochondria and the amplified activation of caspase-8.<ref name="fassignal">{{cite journal| vauthors=Wajant H| title=Connection Map for Fas Signaling Pathway| journal=[[Science Signaling|Science's STKE]]| url=http://stke.sciencemag.org/cgi/cm/CMP_7966| doi=10.1126/stke.3802007tr1| volume=2007| issue=380| pages=tr1| year=2007| s2cid=84909531| access-date=2004-01-01| archive-date=2009-05-03| archive-url=https://web.archive.org/web/20090503010824/http://stke.sciencemag.org/cgi/cm/CMP_7966| url-status=dead}}</ref>

==== Common components ====

Following ''TNF-R1'' and ''Fas'' activation in mammalian cells{{Citation needed|reason=This is only relevant Type II (pancreatic B-cells and hemaetapoetic stem cells), FAS depdnent apoptosis is indepdnent of MOMP|date=October 2020}} a balance between proapoptotic ([[Bcl-2-associated X protein|BAX]],<ref name="bax">{{cite journal | vauthors = Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB | title = Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells | journal = Cell Death and Differentiation | volume = 7 | issue = 1 | pages = 102–111 | date = January 2000 | pmid = 10713725 | doi = 10.1038/sj.cdd.4400597 | doi-access = free | author-link4 = Maria Kavallaris }}</ref> [[BH3 interacting domain death agonist|BID]], [[Bcl-2 homologous antagonist killer|BAK]], or [[Bcl-2-associated death promoter|BAD]]) and anti-apoptotic (''[[Bcl-Xl]]'' and ''[[Bcl-2]]'') members of the ''Bcl-2'' family are established. This balance is the proportion of proapoptotic [[Protein dimer|homodimers]] that form in the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of nonapoptotic cells is incompletely understood, but in general, Bax or Bak are activated by the activation of BH3-only proteins, part of the [[Bcl-2]] family.<ref>{{cite journal | vauthors = Westphal D, Kluck RM, Dewson G | title = Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis | journal = Cell Death and Differentiation | volume = 21 | issue = 2 | pages = 196–205 | date = February 2014 | pmid = 24162660 | pmc = 3890949 | doi = 10.1038/cdd.2013.139 }}</ref>

==== Caspases ====
[[Caspase]]s  play the central role in the transduction of ER apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases (caspases 2, 8, 9, 10, 11, and 12) and effector caspases (caspases 3, 6, and 7). The activation of initiator caspases requires binding to specific oligomeric [[APAF1|activator protein]]. Effector caspases are then activated by these active initiator caspases through [[Proteolysis|proteolytic]] cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program.{{citation needed|date=November 2024}}

==== Caspase-independent apoptotic pathway ====
There also exists a caspase-independent apoptotic pathway that is mediated by AIF ([[apoptosis-inducing factor]]).<ref name="pmid9989411">{{cite journal | vauthors = Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G | display-authors = 6 | title = Molecular characterization of mitochondrial apoptosis-inducing factor | journal = Nature | volume = 397 | issue = 6718 | pages = 441–446 | date = February 1999 | pmid = 9989411 | doi = 10.1038/17135 | s2cid = 204991081 | bibcode = 1999Natur.397..441S }}</ref>

===Apoptosis model in amphibians===

The frog ''[[Xenopus laevis]]'' serves as an ideal model system for the study of the mechanisms of apoptosis. In fact, iodine and thyroxine also stimulate the spectacular apoptosis of the cells of the larval gills, tail and fins in amphibian's metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous [[frog]].<ref>{{cite journal | vauthors = Jewhurst K, Levin M, McLaughlin KA | title = Optogenetic Control of Apoptosis in Targeted Tissues of Xenopus laevis Embryos | journal = Journal of Cell Death | volume = 7 | pages = 25–31 | year = 2014 | pmid = 25374461 | pmc = 4213186 | doi = 10.4137/JCD.S18368 }}</ref><ref>{{Cite journal | vauthors = Venturi S | title = Evolutionary Significance of Iodine |journal=Current Chemical Biology |volume=5 |pages=155–62 |year=2011  |doi=10.2174/187231311796765012 |issue=3| doi-broken-date = 8 January 2025 }}</ref><ref>{{Cite journal |author=Venturi, Sebastiano |title=Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective |journal=Human Evolution |volume= 29 |issue= 1–3 |pages=185–205 |year=2014 |issn=0393-9375}}</ref><ref>{{cite journal | vauthors = Tamura K, Takayama S, Ishii T, Mawaribuchi S, Takamatsu N, Ito M | title = Apoptosis and differentiation of Xenopus tail-derived myoblasts by thyroid hormone | journal = Journal of Molecular Endocrinology | volume = 54 | issue = 3 | pages = 185–192 | date = June 2015 | pmid = 25791374 | doi = 10.1530/JME-14-0327 | doi-access = free }}</ref>