Peroxisomeproliferator-activatedreceptorgammacoactivator-1alpha(PGC-1a)isatissue-specificcoactivatorthatenhancestheactivityofmanynuclearreceptorsandcoordinatestranscriptionalprogramsimportantforenergymetabolismandenergyhomeostasis.InappropriateincreasesinPGC-1aactivityhavebeenlinkedtoanumberofpathologicalconditionsincludingheartfailureanddiabetes.PGC-1aishighlyexpressedinmetabolicallyactivetissuesincludingbrownfat,skeletalmuscleandheart.PGC-1ahasbeenimplicatedinmitochondrialbiogenesisintheheartandincreasedmitochondrialrespirationinbrownfat.PGC-1aisacoactivatorformanyfactorsincluding,CBP,Scr-1,PPARa,GR(glucocorticoidreceptor),THR(thyroidhormonereceptor),severalorphanreceptorsandMEF2.ThispathwayillustratestwoofthecofactorregulatoryfactorsMEF2andPPARa)andanexampleorphanreceptorfeedbackinhibitionloop.Glut4isusedasanexampleofthedownstreamelementsleADIngtochangesinmetabolism.IchidaetaldiscoveredtheERRarepressionofPGC-1a.TheirresultssuggestanovelmechanismoftranscriptionalcontrolwhereinERR-acanfunctionasaspecificmolecularrepressorofPGC-1a.Thissuggeststhatotherco-activatorsmightalsohavespecificrepressors,addinganotherlayerofcombinatorialcomplexityintranscriptionalregulation.CzubrytetalidentifiedPGC-1aasakeytargetoftheMEF2/HDACregulatorypathwayanddemonstratedthispathway"simportanceinmaintenanceofcardiacmitochondrialfunction.ThelinkingofMEF2/HDACprovidesanpotentialexplanationfortheincreaseinmitochondrialnumberobservedinresponsetoCaMKsignaling.

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REFERENCES:BergerI,BieniossekC,SchaffitzelC,HasslerM,SantelliE,RichmondTJ.DirectinteractionofCa2+/calmodulininhibitshistonedeacetylase5repressorcorebindingtomyocyteenhancerfactor2.JBiolChem.2003Mar6[epubaheadofprint]CzubrytMP,McAnallyJ,FishmanGI,OlsonEN.Regulationofperoxisomeproliferator-activatedreceptorgammacoactivator1alpha(PGC-1alpha)andmitochondrialfunctionbyMEF2andHDAC5.ProcNatlAcadSciUSA.2003Feb18;100(4):1711-6.IchidaM,NemotoS,FinkelT.Identificationofaspecificmolecularrepressoroftheperoxisomeproliferator-activatedreceptorgammaCoactivator-1alpha(PGC-1alpha).JBiolChem.2002Dec27;277(52):50991-5.KresslerD,SchreiberSN,KnuttiD,KralliA.ThePGC-1-relatedproteinPERCisaselectivecoactivatorofestrogenreceptoralpha.JBiolChem.2002Apr19;277(16):13918-25.MeredithL.Moore,EdwardsA.ParkandJeanieB.McMillin,Upstreamstimulatoryfactorrepressestheinductionofcarnitinepalmitoyltransferase-IbetaexpressionbyPGC-1.JBiolChem.2003Feb28[epubaheadofprint]SchreiberSN,KnuttiD,BrogliK,UhlmannT,KralliA.TheTranscriptionalCoactivatorPGC-1RegulatestheExpressionandActivityoftheOrphanNuclearReceptorEstrogen-RelatedReceptoralpha(ERRalpha).JBiolChem.2003Mar14;278(11):9013-8.

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