Mitochondriaparticipateinapoptoticsignalingpathwaysthroughthereleaseofmitochondrialproteinsintothecytoplasm.Cytochromec,akeyproteininelectrontransport,isreleasedfrommitochondriainresponsetoapoptoticsignals,andactivatesApaf-1,aproteasereleasedfrommitochondria.ActivatedApaf-1activatescaspase-9andtherestofthecaspasepathway.Smac/DIABLOisreleasedfrommitochondriaandinhibitsIAPproteinsthatnormallyinteractwithcaspase-9toinhibitapoptosis.ApoptosisregulationbyBcl-2familyproteinsoccursasfamilymembersformcomplexesthatenterthemitochondrialmembrane,regulatingthereleaseofcytochromecandotherproteins.TNFfamilyreceptorthatcauseapoptosisdirectlyactivatethecaspasecascade,butcanalsoactivateBid,aBcl-2familymember,whichactivatesmitochondria-mediatedapoptosis.Bax,anotherBcl-2familymember,isactivatedbythispathwaytolocalizetothemitochondrialmembraneandincreaseitspermeABIlity,releasingcytochrecandothermitochondrialproteins.Bcl-2andBcl-xLpreventporeformation,blockingapoptosis.AIF(Apoptosisinducingfactor)isanothermitochondrialfactorthatisreleasedintothecytoplasmtoinduceapoptosis.AIF-inducedapoptosisisimportantduringdevelopmentbutisnotcaspasedependent.

Contributor:GlennCroston,PhD

REFERENCES:HarrisM.H.andThompsonC.B.TheroleoftheBcl-2familyintheregulationofoutermitochondrialmembranepermeability.CellDeathDiffer2000Dec;7(12):1182-91JozaN.etal.Essentialroleofthemitochondrialapoptosis-inducingfactorinprogrammedcelldeath.Nature2001Mar29;410(6828):549-54ShiY.Astructuralviewofmitochondria-mediatedapoptosis.NatStructBiol2001May;8(5):394-401Srinivasula,S.M.AconservedXIAP-interactionmotifincaspase-9andSmac/DIABLOregulatescaspaseactivityandapoptosis.Nature2001Mar1;410(6824):112-6

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