RegulatorsofIronHomeostasis:NewPlayersinMetabolism,CellDeath,andDiseaseAlexanderR.Bogdan1,2,MasakiMiyazawa1,2,KazunoriHashimoto1,andYoshiakiTsuji1,*1DepartmentofBiologicalSciences,NorthCarolinaStateUniversity,CampusBox7633,Raleigh,NC,27695-7633,USAAbstractIronisnecessaryforlife,butcanalsocausecelldeath.Accordingly,cellsevolvedarobust,tightlyregulatedsuiteofgenesformaintainingironhomeostasis.Previousmechanisticstudiesonironhomeostasishavegrantedinsightintotheroleofironinhumanhealthanddisease.Wehighlightnewregulatorsofironmetabolism,includingiron-traffickingproteins[solutecarrierfamily39,SLC39,alsoknownasZRT/IRT-likeprotein,ZIP;andpoly-(rC)-bindingprotein,PCBP]andacargoreceptor(NCOA4)thatiscrucialforreleaseofferritin-boundiron.Wealsodiscussemergingrolesofironinapoptosisandanoveliron-dependentcelldeathpathwaytermed‘ferroptosis’,thedysregulationofironmetabolisminhumanpathologies,andtheuseofironchelatorsincancertherapy.IronHomeostasisIsaComplex,HighlyRegulatedProcessIronisrequiredinavarietyofimportantbiologicalprocessesincludingoxygentransport(ashemeinhemoglobin),DNAbiosynthesis(asacofactorofribonucleotidereductase),andATPgeneration(asacofactorformanyproteinsinthecitricacidcycleandelectrontransportchain);therefore,cellsmustmaintainasufficientamountofiron.However,ironisredox-activeandcangeneratereactiveoxygenspecies(ROS),leadingtooxidativestressandinitiationofsignalingpathwayscrucialforcellsurvivalandcelldeath[1].Tomaintainadequateandsafeamountsofiron,cellsrequirethecoordinationofawidevarietyofgenes,whichtightlycontrolbothintracellular(reviewedin[2,3])andsystemic(reviewedin[4])ironmetabolism.Extensiveresearchbymanygroupshasrevealedkeymechanismsinironhomeostasis(Box1),aswellaslinksbetweenaberrationsinironhomeostasisandhumandisease.Thestudyofironmetabolismcontinuestobeadynamicfield,withmanybreakthroughsandnovelinsightsinthepastseveralyears.Inthisreviewwediscussrecentadvancesinthefunctionandregulationofkeyironmetabolismgenes,including:ferritin(FTH1andFTL),aproteincomple...
