ReviewCell-AutonomousMetabolicReprogramminginHypoxiaLuanaSchito1,*andSergioRey2,*Molecularoxygen(O2)isauniversalelectronacceptorthatenablesATPsyn-thesisthroughmitochondrialrespirationinallmetazoans.Consequently,hyp-oxia(lowO2)hasarisenasanorganizingprincipleforcellularevolution,metabolism,and(patho)biology,elicitingaremarkablepanoplyofmetabolicadaptationsthattriggertranscriptional,translational,post-translational,andepigeneticresponsestodeterminecellularfitness.Inthisreviewwesummarizecurrentandemergingcell-autonomousmolecularmechanismsthatinducehypoxicmetabolicreprogramminginhealthanddisease.O2,MetabolicEvolution,andHomeostasisTheemergenceofphoto-oxygenicunicellularorganismscapableoftransducingsolarenergyintothechemicalenergyofcarbonbonds(�2.44Ga)enabledthetransitionfromananoxictoanoxygenatedatmosphere[1],aprocesswhereinthephotolysisofH2OallowsthereductionofCO2toglucosewhilereleasingmolecularoxygen(O2)asanatmosphericbyproduct(photo-synthesis).TheensuinggradualaccumulationofO2shapedthemetabolicevolutionofances-tralanaerobiccellsandtheendosymbioticacquisitionofaprimordialmitochondrion,allowingaerobicorganismstoutilizethefreeenergyassociatedwiththereductionofO2todrivetheoxidationofglucosetoCO2andH2O(cellularrespiration),thuscompletingabiogeniccyclewhereO2isconsumedandCO2isreturnedtotheatmosphere.Theinnovationofcellularrespirationconferredasignificantenergyadvantageoveranaerobicmetabolism,providing15–16-foldmoreATPpermoleofglucosefullyoxidized.Thissurplusofenergy,availableforbiophysicalandbiochemicalprocesses,isthoughttohavecontributedtotheevolutionofmulticellularlifebysupportingbioticdiversification(seeGlossary)[2].Consistently,metabolicnetworkmodelingrevealedthatO2gaveriseto�103newbiochemicalreactions[3],generatingpreferentiallyhydrophobicmoleculesinvolvedincellsignaling,defenseagainsttoxicbioticfactors,andinantioxidantresponses(e.g.,isoflavonoids,polyunsaturatedfattyacid,andsteroids)[4];indeed,amongthesemolecularmotifs,sterolshavebeenshowntobeakeyO2-dependentre...
