Programmedcelldeathisinducedbymanydifferentfactorsandinvolvesnumeroussignalingpathways,somedependentoncaspaseproteasesandothersthatarecaspaseindependent.LikecytochromeC,AIF(apoptosis-inducingfactor)isaproteinfoundinmitochondriathatisreleasedfrommitochondriabyapoptoticstimuli.WhilecytochromeCislinkedtocaspase-dependentapoptoticsignaling,AIFreleasestimulatescaspase-independentapoptosis,movingintothenucleuswhereitbindsDNA.DNAbindingbyAIFstimulateschromatincondensation,andDNAfragmentation,perhapsthroughrecruitmentofnucleases.DNA-bindingbyAIFoccursthroughadistinctdomainoftheproteininamannerthatdoesnotrelayonspecificDNAsequences.AIFalsohasanotherdomainthatactsasanNADHoxidase,aredoxenzyme.TheNADHoxidaseactivityofAIFisseparablefromitsDNA-bindingactivityandisnotrequiredforAIFtoinduceapoptosis.Inthisrole,AIFprotectsagainstapoptosisratherthaninducingapoptosis.InmicedownregulationoftheAIFgenecreatedharlequinmicewithoxidativedamagetoneuronsandincreasedneuronalcelldeath.LossofAIFalsoincreasedsensitivitytoperoxides,suggestingthatAIFmayactasaperoxidescavenger.ThemechanismbywhichAIFprotectsagainstperoxidedamageisnotclear,butmayinvolveamoreindirectmechanismthandirectperoxidescavengingsincetheenzymedoesnotappeartohavethisactivityinvitro.ElucidatingfurthertheroleofAIFasaredoxenzymewillshedfurtherlightonitsnormalfunctioninmitochondriaaswellasitsroleinapoptosisanddisease.

Contributor:GlennCrostonPh.D.

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