Editing Apoptosis (section)

==Proteolytic caspase cascade: Killing the cell==
Many pathways and signals lead to apoptosis, but these converge on a single mechanism that actually causes the death of the cell. After a cell receives stimulus, it undergoes organized degradation of cellular organelles by activated proteolytic [[caspase]]s. In addition to the destruction of cellular organelles, [[mRNA]] is rapidly and globally degraded by a mechanism that is not yet fully characterized.<ref>{{cite journal | vauthors = Thomas MP, Liu X, Whangbo J, McCrossan G, Sanborn KB, Basar E, Walch M, Lieberman J | display-authors = 6 | title = Apoptosis Triggers Specific, Rapid, and Global mRNA Decay with 3' Uridylated Intermediates Degraded by DIS3L2 | journal = Cell Reports | volume = 11 | issue = 7 | pages = 1079–1089 | date = May 2015 | pmid = 25959823 | pmc = 4862650 | doi = 10.1016/j.celrep.2015.04.026 }}</ref> mRNA decay is triggered very early in apoptosis.

A cell undergoing apoptosis shows a series of characteristic morphological changes. Early alterations include:
# Cell shrinkage and rounding occur because of the retraction of [[lamellipodia]] and the breakdown of the proteinaceous cytoskeleton by caspases.<ref>{{cite journal | vauthors = Böhm I | title = Disruption of the cytoskeleton after apoptosis induction with autoantibodies | journal = Autoimmunity | volume = 36 | issue = 3 | pages = 183–189 | date = May 2003 | pmid = 12911286 | doi = 10.1080/0891693031000105617 | s2cid = 37887253 }}</ref>
# The cytoplasm appears dense, and the organelles appear tightly packed.{{citation needed|date=November 2024}}
# Chromatin undergoes condensation into compact patches against the [[Nuclear membrane|nuclear envelope]] (also known as the perinuclear envelope) in a process known as [[pyknosis]], a hallmark of apoptosis.<ref name="nuclearapopt">{{cite journal | vauthors = Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, Costantini P, Ferri KF, Irinopoulou T, Prévost MC, Brothers G, Mak TW, Penninger J, Earnshaw WC, Kroemer G | display-authors = 6 | title = Two distinct pathways leading to nuclear apoptosis | journal = The Journal of Experimental Medicine | volume = 192 | issue = 4 | pages = 571–580 | date = August 2000 | pmid = 10952727 | pmc = 2193229 | doi = 10.1084/jem.192.4.571 }}</ref><ref name="chromatindegrad">{{cite journal | vauthors = Kihlmark M, Imreh G, Hallberg E | title = Sequential degradation of proteins from the nuclear envelope during apoptosis | journal = Journal of Cell Science | volume = 114 | issue = Pt 20 | pages = 3643–3653 | date = October 2001 | pmid = 11707516 | doi = 10.1242/jcs.114.20.3643 }}</ref>
# The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a process referred to as [[karyorrhexis]]. The nucleus breaks into several discrete ''chromatin bodies'' or ''nucleosomal units'' due to the degradation of DNA.<ref name="nuclearfrag">{{cite journal | vauthors = Nagata S | title = Apoptotic DNA fragmentation | journal = Experimental Cell Research | volume = 256 | issue = 1 | pages = 12–18 | date = April 2000 | pmid = 10739646 | doi = 10.1006/excr.2000.4834 }}</ref>

Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize on classical histology sections. During karyorrhexis, [[endonuclease]] activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on [[agar]] gel after [[electrophoresis]].<ref>{{cite journal | vauthors = Gong J, Traganos F, Darzynkiewicz Z | title = A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry | journal = Analytical Biochemistry | volume = 218 | issue = 2 | pages = 314–319 | date = May 1994 | pmid = 8074286 | doi = 10.1006/abio.1994.1184 }}</ref> Tests for [[DNA laddering]] differentiate apoptosis from [[Ischemia|ischemic]] or toxic cell death.<ref name=Iwata>{{cite journal | vauthors = Iwata M, Myerson D, Torok-Storb B, Zager RA | title = An evaluation of renal tubular DNA laddering in response to oxygen deprivation and oxidant injury | journal = Journal of the American Society of Nephrology | volume = 5 | issue = 6 | pages = 1307–1313 | date = December 1994 | pmid = 7893995 | doi = 10.1681/ASN.V561307 | doi-access = free }}</ref>

===Apoptotic cell disassembly===
[[File:Apoptotic cell disassembly.png|thumb|500px|Different steps in apoptotic cell disassembly<ref>{{Cite journal| vauthors = Smith A, Parkes MA, Atkin-Smith GK, Tixeira R, Poon IK |title=Cell disassembly during apoptosis|journal=WikiJournal of Medicine|language=en|volume=4|issue=1|doi=10.15347/wjm/2017.008|year=2017|doi-access=free}}</ref>]]
Before the apoptotic cell is disposed of, there is a process of disassembly. There are three recognized steps in apoptotic cell disassembly:<ref name="pmid28102458">{{cite journal | vauthors = Tixeira R, Caruso S, Paone S, Baxter AA, Atkin-Smith GK, Hulett MD, Poon IK | title = Defining the morphologic features and products of cell disassembly during apoptosis | journal = Apoptosis | volume = 22 | issue = 3 | pages = 475–477 | date = March 2017 | pmid = 28102458 | doi = 10.1007/s10495-017-1345-7 | s2cid = 34648758 }}</ref>
# Membrane blebbing: The cell membrane shows irregular buds known as [[bleb (cell biology)|blebs]]. Initially these are smaller surface blebs. Later these can grow into larger so-called dynamic membrane blebs.<ref name="pmid28102458"/> An important regulator of apoptotic cell membrane blebbing is [[ROCK1]] (rho associated coiled-coil-containing protein kinase 1).<ref name="pmid11283606">{{cite journal | vauthors = Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF | title = Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I | journal = Nature Cell Biology | volume = 3 | issue = 4 | pages = 339–345 | date = April 2001 | pmid = 11283606 | doi = 10.1038/35070009 | s2cid = 2537726 }}</ref><ref name="pmid11283607">{{cite journal | vauthors = Sebbagh M, Renvoizé C, Hamelin J, Riché N, Bertoglio J, Bréard J | title = Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing | journal = Nature Cell Biology | volume = 3 | issue = 4 | pages = 346–352 | date = April 2001 | pmid = 11283607 | doi = 10.1038/35070019 | s2cid = 36187702 }}</ref>
# Formation of membrane protrusions: Some cell types, under specific conditions, may develop different types of long, thin extensions of the cell membrane called membrane protrusions. Three types have been described: [[microtubule]] spikes, '''apoptopodia''' (''feet of death''), and '''beaded apoptopodia''' (the latter having a beads-on-a-string appearance).<ref name="pmid16723742">{{cite journal | vauthors = Moss DK, Betin VM, Malesinski SD, Lane JD | title = A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation | journal = Journal of Cell Science | volume = 119 | issue = Pt 11 | pages = 2362–2374 | date = June 2006 | pmid = 16723742 | pmc = 1592606 | doi = 10.1242/jcs.02959 }}</ref><ref name="pmid24646995">{{cite journal | vauthors = Poon IK, Chiu YH, Armstrong AJ, Kinchen JM, Juncadella IJ, Bayliss DA, Ravichandran KS | title = Unexpected link between an antibiotic, pannexin channels and apoptosis | journal = Nature | volume = 507 | issue = 7492 | pages = 329–334 | date = March 2014 | pmid = 24646995 | pmc = 4078991 | doi = 10.1038/nature13147 | bibcode = 2014Natur.507..329P }}</ref><ref name="pmid26074490">{{cite journal | vauthors = Atkin-Smith GK, Tixeira R, Paone S, Mathivanan S, Collins C, Liem M, Goodall KJ, Ravichandran KS, Hulett MD, Poon IK | display-authors = 6 | title = A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure | journal = Nature Communications | volume = 6 | pages = 7439 | date = June 2015 | pmid = 26074490 | pmc = 4490561 | doi = 10.1038/ncomms8439 | bibcode = 2015NatCo...6.7439A }}</ref> [[Pannexin 1]] is an important component of membrane channels involved in the formation of apoptopodia and beaded apoptopodia.<ref name="pmid24646995"/>
# [[Fragmentation (cell biology)|Fragmentation]]: The cell breaks apart into multiple [[Vesicle (biology and chemistry)|vesicles]] called ''apoptotic bodies'', which undergo [[phagocytosis]]. The plasma membrane protrusions may help bring apoptotic bodies closer to [[phagocyte]]s.{{citation needed|date=November 2024}}

===Removal of dead cells===
The removal of dead cells by neighboring phagocytic cells has been termed [[efferocytosis]].<ref name="pmid16778289">{{cite journal | vauthors = Vandivier RW, Henson PM, Douglas IS | title = Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease | journal = Chest | volume = 129 | issue = 6 | pages = 1673–1682 | date = June 2006 | pmid = 16778289 | doi = 10.1378/chest.129.6.1673 }}</ref>
Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as [[phosphatidylserine]], on their cell surface.<ref name="Phosphatidylserine">{{cite journal | vauthors = Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA | title = Phosphatidylserine receptor is required for clearance of apoptotic cells | journal = Science | volume = 302 | issue = 5650 | pages = 1560–1563 | date = November 2003 | pmid = 14645847 | doi = 10.1126/science.1087621 | s2cid = 36252352 | bibcode = 2003Sci...302.1560O }}</ref> Phosphatidylserine is normally found on the inner leaflet surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as [[phospholipid scramblase|scramblase]].<ref name="phago2">{{cite journal | vauthors = Wang X, Wu YC, Fadok VA, Lee MC, Gengyo-Ando K, Cheng LC, Ledwich D, Hsu PK, Chen JY, Chou BK, Henson P, Mitani S, Xue D | display-authors = 6 | title = Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12 | journal = Science | volume = 302 | issue = 5650 | pages = 1563–1566 | date = November 2003 | pmid = 14645848 | doi = 10.1126/science.1087641 | url = http://ntur.lib.ntu.edu.tw/handle/246246/161415 | access-date = 2017-02-26 | url-status = dead | s2cid = 25672278 | bibcode = 2003Sci...302.1563W | archive-url = https://web.archive.org/web/20210414033822/http://ntur.lib.ntu.edu.tw/handle/246246/161415 | archive-date = 2021-04-14 }}</ref> These molecules mark the cell for [[phagocytosis]] by cells possessing the appropriate receptors, such as macrophages.<ref name="phago1">{{cite journal | vauthors = Savill J, Gregory C, Haslett C | title = Cell biology. Eat me or die | journal = Science | volume = 302 | issue = 5650 | pages = 1516–1517 | date = November 2003 | pmid = 14645835 | doi = 10.1126/science.1092533 | hdl-access = free | s2cid = 13402617 | hdl = 1842/448 }}</ref> The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an [[inflammatory response]].<ref name="phago1B">{{cite book |vauthors=Krysko DV, Vandenabeele P |veditors=Krysko DV, Vandenabeele P |title=Phagocytosis of dying cells: from molecular mechanisms to human diseases |url=https://www.springer.com/biomed/cancer/book/978-1-4020-9292-3 |isbn=978-1-4020-9292-3 |date=2009-01-14 |publisher=Springer |doi=10.1007/978-1-4020-9293-0 |access-date=2017-08-28 |archive-date=2022-04-30 |archive-url=https://web.archive.org/web/20220430005601/https://link.springer.com/book/10.1007/978-1-4020-9293-0 |url-status=live }}</ref> During apoptosis cellular RNA and DNA are separated from each other and sorted to different apoptotic bodies; separation of RNA is initiated as nucleolar segregation.<ref>{{cite journal | vauthors = Halicka HD, Bedner E, Darzynkiewicz Z | title = Segregation of RNA and separate packaging of DNA and RNA in apoptotic bodies during apoptosis | journal = Experimental Cell Research | volume = 260 | issue = 2 | pages = 248–256 | date = November 2000 | pmid = 11035919 | doi = 10.1006/excr.2000.5027 }}</ref>