Editing Apoptosis (section)

===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}}