isolatedTOMcomplexes[4].Thisobser-vationunderscoresthepivotalroleofUbx2asacomponentofanovelquality-controlstrategythatmonitorsthefidelityofTOM-complex-mediatedimport.Thisreportedmachinerywasdesignatedasmitochondrialproteintranslocation-associateddegradation(mitoTAD)pathway[4].WhiletheelegantworkbyMårtenssonandcolleaguesrevealedtheactivetargetingofubiquitinatedmisfoldedtrappedprecursorproteinstotheproteasomefordegrada-tionbytheso-calledmitoTADpathway(Figure1)[4],manysignificantimplicationsofthisworkremaintobeaddressed.First,itisimportanttounderstandhowUbx2recognizesatrappedprecursorproteinfragmentintheTOMcomplexchannel.Additionally,elucidatinghowthispathwayisubiquitindependentandfur-therdefiningtheconstituentsoftherecog-nitionmachinery(E3ubiquitinligase)andthepreciseubiquitinsignalsthatfine-tunethemitoTADmachinerywithintheTOMcomplexwillbeanimportantfuturere-searchavenue.Intriguingly,theobserva-tionthattheERandmitochondriaexploitthesameregulator(Ubx2)forqualitycontrolsuggeststhattheseprocessesmightbesubjecttocoregulation.Under-standinghowthismightberelatedtotheintimateconnectionbetweenmitochondriaandtheERatcontactsitesbetweentheseorganellesisanopenquestion.Furthermore,itwillalsobeimportanttodeterminewhetherthemitoTADpathwayanditsinterconnectionwiththeERADpathwayareconservedinmammaliancells.ItwillalsobeinterestingtoexplorewhetherandhowthemitoTADpathwaymightberelatedtomitophagy.OnecanenvisionthatfailureofthemitochondrialTOM-complexmachineryuponaccumulationofmisfoldedprecursorproteinsmayculminateinmitochondrialderegulationifthetrappedmisfoldedproteinlevelsoverwhelmthemitoTADproteolyticdegra-dationcapacity;possiblytriggeringmoreextensiveresponsessuchasmitophagy.Indeed,itwouldbecrucialtoinvestigatethemolecularconnectionbetweenthemitoTADpathwayandothermitochondrialquality-controlregulatorsthatareactivateduponstress.Ofnote,theauthorsobservedthattheablationoftwocrucialmitochon-drialquality-controlregulators,Vms1andMsp1,fromcellsthataredeficientinUbx2[4],resultsinimpairedm...
