Просмотр кода страницы Английская Википедия:Apoptosis-inducing factor

{{Английская Википедия/Панель перехода}}
{{Short description|Protein family}}
{{protein
| Name = [[AIFM1|apoptosis-inducing factor, mitochondrion-associated, 1]]
| caption = Crystallographic structure of the human apoptosis inducing factor (rainbow color cartoon diagram, [[N-terminus]] = blue, [[C-terminus]] = red).<ref name="pmid12198487">{{PDB|1M6I}}; {{cite journal | vauthors = Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H | title = DNA binding is required for the apoptogenic action of apoptosis inducing factor | journal = Nature Structural Biology | volume = 9 | issue = 9 | pages = 680–4 | date = September 2002 | pmid = 12198487 | doi = 10.1038/nsb836 | s2cid = 7819466 }}</ref>
| image = apoptosis inducing factor.png
| width = 
| HGNCid = 8768
| Symbol = [[AIFM1]]
| AltSymbols = PDCD8
| EntrezGene = 9131
| OMIM = 300169
| RefSeq = NM_004208
| UniProt = O95831
| PDB = 
| ECnumber = 
| Chromosome = X
| Arm = q
| Band = 25
| LocusSupplementaryData = -q26
}}
'''Apoptosis inducing factor''' is involved in initiating a caspase-independent pathway of [[apoptosis]] (positive intrinsic regulator of apoptosis) by causing DNA fragmentation and chromatin condensation. Apoptosis inducing factor is a [[flavoprotein]].<ref name="pmid19723031">{{cite journal | vauthors = Joza N, Pospisilik JA, Hangen E, Hanada T, Modjtahedi N, Penninger JM, Kroemer G | title = AIF: not just an apoptosis-inducing factor | journal = Annals of the New York Academy of Sciences | volume = 1171 | pages = 2–11 | date = August 2009 | issue = 1 | pmid = 19723031 | doi = 10.1111/j.1749-6632.2009.04681.x | bibcode = 2009NYASA1171....2J | s2cid = 35011873 }}</ref> It also acts as an [[NADH]] oxidase. Another AIF function is to regulate the permeability of the mitochondrial membrane upon apoptosis. Normally it is found behind the outer membrane of the mitochondrion and is therefore secluded from the nucleus. However, when the mitochondrion is damaged, it moves to the cytosol and to the nucleus. Inactivation of AIF leads to resistance of embryonic stem cells to death following the withdrawal of growth factors indicating that it is involved in apoptosis.<ref name="pmid19723031"/><ref name="pmid12022952">{{cite journal | vauthors = Candé C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G | title = Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria | journal = Biochimie | volume = 84 | issue = 2–3 | pages = 215–22 | year = 2002 | pmid = 12022952 | doi = 10.1016/S0300-9084(02)01374-3 }}</ref>

== Function ==

Apoptosis Inducing Factor (AIF) is a protein that triggers [[chromatin condensation]] and [[DNA fragmentation]] in a cell in order to induce programmed cell death. The mitochondrial AIF protein was found to be a [[caspase]]-independent death effector that can allow independent nuclei to undergo apoptotic changes. The process triggering apoptosis starts when the mitochondrion releases AIF, which exits through the mitochondrial membrane, enters the cytosol, and moves to the nucleus of the cell, where it signals the cell to condense its chromosomes and fragment its DNA molecules in order to prepare for cell death. Recently, researchers have discovered that the activity of AIF depends on the type of cell, the apoptotic insult, and its DNA-binding ability. AIF also plays a significant role in the [[electron transport chain#Electron transport chains in mitochondria|mitochondrial respiratory chain]] and metabolic [[redox]] reactions.<ref name="pmid20138767">{{cite journal | vauthors = Hangen E, Blomgren K, Bénit P, Kroemer G, Modjtahedi N | title = Life with or without AIF | journal = Trends in Biochemical Sciences | volume = 35 | issue = 5 | pages = 278–87 | date = May 2010 | pmid = 20138767 | doi = 10.1016/j.tibs.2009.12.008 }}</ref>

== Synthesis ==

The AIF protein is located across 16 [[exon]]s on the [[X chromosome]] in humans. AIF1 (the most abundant type of AIF) is translated in the cytosol and recruited to the [[mitochondrial membrane]] and [[intermembrane space]] by its N-terminal [[target peptide#Mitochondria|mitochondrial localization signal]] (MLS). Inside the mitochondrion, AIF folds into its functional configuration with the help of the cofactor [[flavin adenine dinucleotide]] (FAD).

A protein called [[HLA-B associated transcript 3|Scythe]] (BAT3), which is used to regulate organogenesis, can increase the AIF lifetime in the cell. As a result, decreased amounts of Scythe lead to a quicker fragmentation of AIF. The X-linked inhibitor of apoptosis ([[XIAP]]) has the power to influence the half-life of AIF along with Scythe. Together, the two do not affect the AIF attached to the inner mitochondrial membrane, however they influence the stability of AIF once it exits the mitochondrion.<ref name="pmid20138767"/>

== Role in mitochondria ==

It was thought that if a recombinant version of AIF lacked the first N-terminal 120 amino acids of the protein, then AIF would function as an NADH and NADPH oxidase. However, it was instead discovered that recombinant AIF that do not have the last 100 N-terminal amino acids have limited NADP and NADPH oxidase activity. Therefore, researchers concluded that the AIF N-terminus may function in interactions with other proteins or control AIF redox reactions and substrate specificity.

Mutations of AIF due to deletions have stimulated the creation of the mouse model of complex I deficiency. Complex I deficiency is the reason behind over thirty percent of human mitochondrial diseases. For example, complex I mitochondriopathies mostly affect infants by causing symptoms such as seizures, blindness, deafness, etc. These AIF-deficient mouse models are important for fixing complex I deficiencies. The identification of AIF-interacting proteins in the inner mitochondrial membrane and intermembrane space will help researchers identify the mechanism of the signalling pathway that monitors the function of AIF in the mitochondria.<ref name="pmid20138767"/>

== Isozymes ==

Human genes encoding apoptosis inducing factor isozymes include:
* [[AIFM1]]
* [[AIFM2]]
* [[AIFM3]]

== Evolution ==
The apoptotic function of AIFs has been shown in organisms belonging to different eukaryotic organisms including mentioned above human factors: AIM1, AIM2, and AIM3 (Xie ''et al.'', 2005), yeast factors NDI1 and AIF1 as well as AIF of Tetrahymena.  Phylogenetic analysis indicates that the divergence of the AIFM1, AIFM2, AIFM3, and NDI sequences occurred before the divergence of eukaryotes.<ref>{{cite journal | vauthors = Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S | title = Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes | journal = G3 | volume = 8 | issue = 6 | pages = 2121–2134 | date = May 2018 | pmid = 29703784 | pmc = 5982838 | doi = 10.1534/g3.118.200295 }}</ref>

== Role in cancer ==
Despite an involvement in cell death, AIF plays a contributory role to the growth and aggressiveness of a variety of cancer types including [[Colorectal cancer|colorectal]], [[Prostate cancer|prostate]], and [[Pancreatic cancer|pancreatic]] cancers through its NADH oxidase activity. AIF enzymatic activity regulates metabolism but can also increase [[Reactive oxygen species|ROS]] levels promoting oxidative stress activated signaling molecules including the [[Mitogen-activated protein kinase|MAPKs]]. AIF-mediated redox signaling promotes the activation of [[JNK|JNK1]], which in turn can trigger the [[Epithelial-mesenchymal transition|cadherin switch]].<ref>{{cite journal | vauthors = Urbano A, Lakshmanan U, Choo PH, Kwan JC, Ng PY, Guo K, Dhakshinamoorthy S, Porter A | title = AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells | journal = The EMBO Journal | volume = 24 | issue = 15 | pages = 2815–26 | date = August 2005 | pmid = 16001080 | doi = 10.1038/sj.emboj.7600746 | pmc = 1182241 }}</ref><ref>{{cite journal | vauthors = Lewis EM, Wilkinson AS, Jackson JS, Mehra R, Varambally S, Chinnaiyan AM, Wilkinson JC | title = The enzymatic activity of apoptosis-inducing factor supports energy metabolism benefiting the growth and invasiveness of advanced prostate cancer cells | journal = The Journal of Biological Chemistry | volume = 287 | issue = 52 | pages = 43862–75 | date = December 2012 | pmid = 23118229 | doi = 10.1074/jbc.M112.407650 | pmc = 3527969 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Scott AJ, Wilkinson AS, Wilkinson JC | title = Basal metabolic state governs AIF-dependent growth support in pancreatic cancer cells | journal = BMC Cancer | volume = 16 | pages = 286 | date = April 2016 | pmid = 27108222 | doi = 10.1186/s12885-016-2320-3 | pmc = 4841948 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Scott AJ, Walker SA, Krank JJ, Wilkinson AS, Johnson KM, Lewis EM, Wilkinson JC | title = AIF promotes a JNK1-mediated cadherin switch independently of respiratory chain stabilization | journal = The Journal of Biological Chemistry | volume = 293 | issue = 38 | pages = 14707–14722 | date = September 2018 | pmid = 30093403 | doi = 10.1074/jbc.RA118.004022 | pmc=6153284| doi-access = free }}</ref>

== See also ==
* [[Apoptosis]]
* [[Parthanatos]]

== References ==
{{Reflist}}

== External links ==
* {{MeshName|Apoptosis+inducing+factor}}

{{Flavoproteins}}
{{Apoptosis signaling pathway}}
{{Cell signaling}}

{{DEFAULTSORT:Apoptosis-Inducing Factor}}
[[Category:Programmed cell death]]
[[Category:Cell signaling]]
[[Category:Apoptosis]]
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