Editing Mitochondrion (section)

=== Programmed cell death and innate immunity ===
{{Further|Programmed cell death#Intrinsic Pathway}}

[[Programmed cell death]] (PCD) is crucial for various physiological functions, including organ development and cellular homeostasis. It serves as an intrinsic mechanism to prevent [[malignant transformation]] and plays a fundamental role in [[Immune system|immunity]] by aiding in antiviral defense, pathogen elimination, inflammation, and immune cell recruitment.<ref>{{cite journal | vauthors = Riera Romo M | title = Cell death as part of innate immunity: Cause or consequence? | journal = Immunology | volume = 163 | issue = 4 | pages = 399–415 | date = August 2021 | pmid = 33682112 | pmc = 8274179 | doi = 10.1111/imm.13325 }}</ref>

Mitochondria have long been recognized for their central role in the [[Apoptosis#Intrinsic pathway|intrinsic pathway]] of [[apoptosis]], a form of PCD.<ref>{{cite journal | vauthors = Green DR | title = Apoptotic pathways: the roads to ruin | journal = Cell | volume = 94 | issue = 6 | pages = 695–698 | date = September 1998 | pmid = 9753316 | doi = 10.1016/S0092-8674(00)81728-6 | doi-access = free }}</ref> In recent decades, they have also been identified as a signalling hub for much of the [[innate immune system]].<ref name="Bahat-2021">{{cite journal | vauthors = Bahat A, MacVicar T, Langer T | title = Metabolism and Innate Immunity Meet at the Mitochondria | language = English | journal = Frontiers in Cell and Developmental Biology | volume = 9 | pages = 720490 | date = 2021-07-27 | pmid = 34386501 | doi = 10.3389/fcell.2021.720490 | doi-access = free | pmc = 8353256 }}</ref> The [[Symbiogenesis|endosymbiotic origin]] of mitochondria distinguishes them from other cellular components, and the exposure of mitochondrial elements to the [[cytosol]] can trigger the same pathways as infection markers. These pathways lead to [[apoptosis]], [[autophagy]], or the induction of proinflammatory genes.<ref name="Murphy-2024">{{cite journal | vauthors = Murphy MP, O'Neill LA | title = A break in mitochondrial endosymbiosis as a basis for inflammatory diseases | journal = Nature | volume = 626 | issue = 7998 | pages = 271–279 | date = February 2024 | pmid = 38326590 | doi = 10.1038/s41586-023-06866-z | bibcode = 2024Natur.626..271M | url = https://www.repository.cam.ac.uk/handle/1810/364692 }}</ref><ref name="Bahat-2021" />

Mitochondria contribute to apoptosis by releasing [[Cytochrome c|cytochrome ''c'']], which directly induces the formation of [[apoptosome]]s. Additionally, they are a source of various [[damage-associated molecular pattern]]s (DAMPs). These DAMPs are often recognised by the same [[Pattern recognition receptor|pattern-recognition receptors]] (PRRs) that respond to [[pathogen-associated molecular pattern]]s (PAMPs) during infections.{{refn|{{cite journal | vauthors = Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P | title = Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation | journal = Trends in Immunology | volume = 32 | issue = 4 | pages = 157–164 | date = April 2011 | pmid = 21334975 | doi = 10.1016/j.it.2011.01.005 | url = https://lirias.kuleuven.be/bitstream/123456789/632510/2/Krysko%20et%20al%20_21-09-10.doc }}; cited in<ref name="Murphy-2024" />}} For example, mitochondrial mtDNA resembles bacterial DNA due to its lack of [[CpG site|CpG]] methylation and can be detected by [[Toll-like receptor 9]] and [[CGAS–STING cytosolic DNA sensing pathway|cGAS]].{{refn|{{cite journal | vauthors = Riley JS, Tait SW | title = Mitochondrial DNA in inflammation and immunity | journal = EMBO Reports | volume = 21 | issue = 4 | pages = e49799 | date = April 2020 | pmid = 32202065 | pmc = 7132203 | doi = 10.15252/embr.201949799 }}; cited in<ref name="Murphy-2024" />}} [[DsRNA|Double-stranded RNA]]  (dsRNA), produced due to bidirectional mitochondrial transcription, can activate viral sensing pathways through [[RIG-I-like receptor]]s.{{refn|{{cite journal | vauthors = Seth RB, Sun L, Ea CK, Chen ZJ | title = Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3 | journal = Cell | volume = 122 | issue = 5 | pages = 669–682 | date = September 2005 | pmid = 16125763 | doi = 10.1016/j.cell.2005.08.012 }}; cited in<ref name="Murphy-2024" />}} Additionally, the ''N''-formylation of [[Human mitochondrial genetics|mitochondrial proteins]], similar to that of bacterial proteins, can be recognized by [[formyl peptide receptor]]s.{{refn|{{cite journal | vauthors = Dorward DA, Lucas CD, Doherty MK, Chapman GB, Scholefield EJ, Conway Morris A, Felton JM, Kipari T, Humphries DC, Robb CT, Simpson AJ, Whitfield PD, Haslett C, Dhaliwal K, Rossi AG | title = Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome | journal = Thorax | volume = 72 | issue = 10 | pages = 928–936 | date = October 2017 | pmid = 28469031 | pmc = 5738532 | doi = 10.1136/thoraxjnl-2017-210030 }}; cited in<ref name="Murphy-2024" />}}{{refn|{{cite journal | vauthors = Cai N, Gomez-Duran A, Yonova-Doing E, Kundu K, Burgess AI, Golder ZJ, Calabrese C, Bonder MJ, Camacho M, Lawson RA, Li L, Williams-Gray CH, Di Angelantonio E, Roberts DJ, Watkins NA, Ouwehand WH, Butterworth AS, Stewart ID, Pietzner M, Wareham NJ, Langenberg C, Danesh J, Walter K, Rothwell PM, Howson JM, Stegle O, Chinnery PF, Soranzo N | title = Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases | journal = Nature Medicine | volume = 27 | issue = 9 | pages = 1564–1575 | date = September 2021 | pmid = 34426706 | doi = 10.1038/s41591-021-01441-3 | first14 = Emanuele | first15 = David J. | hdl = 10261/249231 | hdl-access = free }}; cited in<ref name="Murphy-2024" />}}

Normally, these mitochondrial components are sequestered from the rest of the cell but are released following mitochondrial membrane permeabilization during apoptosis or passively after mitochondrial damage. However, mitochondria also play an active role in innate immunity, releasing mtDNA in response to metabolic cues.<ref name="Bahat-2021" /> Mitochondria are also the [[Subcellular localization|localization site]] for immune and apoptosis regulatory proteins, such as [[Apoptosis regulator BAX|BAX]], [[Mitochondrial antiviral-signaling protein|MAVS]] (located on the [[Mitochondrion#Outer membrane|outer membrane]]), and [[NLRX1]] (found in the [[Mitochondrion#Matrix|matrix]]). These proteins are modulated by the mitochondrial metabolic status and mitochondrial dynamics.<ref name="Bahat-2021" />{{refn|{{cite journal | vauthors = Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, Chang Y, Chen Y, Lu Y, Zeng H, Cai Z, Han F, Xu C, Jin G, Sun L, Pan BS, Lai SW, Hsu CC, Xu J, Chen ZZ, Li HY, Seth P, Hu J, Zhang X, Li H, Lin HK | title = Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS | journal = Cell | volume = 178 | issue = 1 | pages = 176–189.e15 | date = June 2019 | pmid = 31155231 | pmc = 6625351 | doi = 10.1016/j.cell.2019.05.003 }}; cited in<ref name="Bahat-2021" />}}{{refn|{{cite journal | vauthors = Pourcelot M, Arnoult D | title = Mitochondrial dynamics and the innate antiviral immune response | journal = The FEBS Journal | volume = 281 | issue = 17 | pages = 3791–3802 | date = September 2014 | pmid = 25051991 | doi = 10.1111/febs.12940 }}; cited in<ref name="Bahat-2021" />}}