ORIGINALARTICLEKruppa,A.J.etal.MyosinVI-dependentactincagesencapsulateParkin-positivedamagedmitochondria.Dev.Cellhttps://doi.org/10.1016/j.devcel.2018.01.007(2018)V.Summersby/MacmillanPublishersLimitedDuringmitophagy,damagedmitochondriaareubiquitylatedbytheE3ubiquitinligaseParkinandsubsequentlyboundbyautophagyreceptorsandengulfedbyautophagosomesfordegradation.Theremovalofdefectivemitochondriaisessentialforcellularhomeostasis,buthowefficiencyofmitophagyisachievedisunclear.Kruppaetal.nowidentifymyosinVI(MYO6)asanewregulatorofmitophagy.MYO6hasbeenpreviouslyshowntointeractwithubiquitinandmitophagyreceptors,raisingthepossibilitythatitisinvolvedinmitophagy.Indeed,followingdrug-inducedmitochondriadepolarization(apotenttriggerofParkin-mediatedmitophagy)inculturedhumanepithelialkidneycells(HEK293cells),MYO6colocalizedwithParkinonmitochondria,whereasitisnormallyfoundaroundintracellularvesiclesinthecytosolandattheplasmamembrane.Importantly,MYO6recruitmenttomitochondriawasunaffectedbytheknockdownofmitophagyreceptors,butwasstronglyimpairedwhenitsubiquitin-bindingregionwasmutated.Thus,followingdepolarization,MYO6istargetedtomitochondriabybindingtoubiquitin.Apartfromservingasactin-basedmotors,myosinsalsofunctioninactincytoskeletonreorganization.WithintwohoursaftermitochondrialdepolarizationinHEK293cells,actinformedcagesaroundfragmentedmitochondria;thisencagingwasblockedbyectopicexpressionoftheMYO6tail,whichcannotinteractwithactin.Actin-cagedmitochondriaweresmallerthanmitochondriadevoidofsuchcages,butectopicexpressionoftheMYO6tailorinterferencewithactinnucleationincreasedmitochondrialsizeandcausedmitochondrialre-fusion.Thus,MYO6-mediatedactincagessequestermitochondriadestinedformitophagyandpreventtheirre-integrationintothefunctionalmitochondrialnetwork.Mouseembryonicfibroblasts(MEFs)inwhichMyo6wasdeletedhadincreasednumbersofmitochondria-containingautophagosomesinducedbymitochondrialdepolarization,indicatingthatinadditiontosequesteringdamagedmitochondriabeforeautophagosomalengulfment,MYO6alsopromotesthetimelyclearanceofmitochondria-loadedautophagosomes.MitochondrialmasswasincreasedinMYO6-deficientMEFs,butmitochondrialrespirationwascompromised.MitochondrialfunctionwasalsoimpairedinMYO6-depletedHEK293cells,astheydidnotgrowinmediumcontainingthesugargalactose,whichrequirescellstorelyonmitochondrialrespirationforenergyproduction.Insummary,MYO6supportstheclearanceofdysfunctionalmitochondriabymitophagytomaintainahealthymitochondrialnetwork,anditdoesso,atleastinpart,byinducingentrapmentofdamagedmitochondriaintoactincages.Thesefindingsprovidenovelinsightsintomitophagyregulationbycytoskeletalcomponents.PaulinaStrzyzAUTOPHAGYMitochondriaencagedMYO6‑mediatedactincagessequestermitochondriaRESEARCHHIGHLIGHTSNATUREREVIEWS|MOLECULARCELLBIOLOGYwww.nature.com/nrmNatureReviewsMolecularCellBiology|Publishedonline28Feb2018;doi:10.1038/nrm.2018.16©2018MacmillanPublishersLimited,partofSpringerNature.Allrightsreserved.
