medium33669.com

REVIEWARTICLEpublished:31July2014doi:10.
3389/fphys.
2014.
00282MitochondrialandcellularmechanismsformanaginglipidexcessMiguelA.
Aon*,NirajBhattandSoniaC.
CortassaDivisionofCardiology,DepartmentofMedicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,USAEditedby:PaoloBernardi,UniversityofPadova,ItalyReviewedby:NinaKaludercic,NationalResearchCouncilofItaly,ItalyChristianFrezza,Hutchison/MRCResearchInstitute,UKPaoloBernardi,UniversityofPadova,Italy*Correspondence:MiguelA.
Aon,DivisionofCardiology,DepartmentofMedicine,JohnsHopkinsUniversitySchoolofMedicine,720RutlandAvenue,RossBldg.
1059,Baltimore,MD21205,USAe-mail:maon1@jhmi.
eduCurrentscienticdebatescenterontheimpactoflipidsandmitochondrialfunctionondiverseaspectsofhumanhealth,nutritionanddisease,amongthemtheassociationoflipotoxicitywiththeonsetofinsulinresistanceinskeletalmuscle,andwithheartdysfunctioninobesityanddiabetes.
Mitochondriaplayafundamentalroleinagingandinprevalentacuteorchronicdiseases.
Lipidsaremainmitochondrialfuelshoweverthesemoleculescanalsobehaveasuncouplersandinhibitorsofoxidativephosphorylation.
Knowledgeaboutthefunctionalcompositionofthesecontradictoryeffectsandtheirimpactonmitochondrial-cellularenergetics/redoxstatusisincomplete.
Cellsstorefattyacids(FAs)astriacylglycerolandpackagethemintocytoplasmiclipiddroplets(LDs).
NewemergingdatashowstheLDasahighlydynamicstoragepoolofFAsthatcanbeusedforenergyreserve.
LipidexcesspackagingintoLDscanbeseenasanadaptiveresponsetofulllingenergysupplywithouthinderingmitochondrialorcellularredoxstatusandkeepinglowconcentrationoflipotoxicintermediates.
Hereinwereviewthemechanismsofactionandutilizationoflipidsbymitochondriareportedinliver,heartandskeletalmuscleunderrelevantphysiologicalsituations,e.
g.
,exercise.
Wereportonperilipins,afamilyofproteinsthatassociatewithLDsinresponsetoloadingofcellswithlipids.
Evidenceshowingthatinadditiontophysicalcontact,mitochondriaandLDsexhibitmetabolicinteractionsispresentedanddiscussed.
Ahypotheticalmodelofchanneledlipidutilizationbymitochondriaisproposed.
Directdeliveryandchanneledprocessingoflipidsinmitochondriacouldrepresentareliableandefcientwaytomaintainreactiveoxygenspecies(ROS)withinlevelscompatiblewithsignalingwhileensuringrobustandreliableenergysupply.
Keywords:palmitoylCoA,lipiddroplet,perilipin,beta-oxidation,redoxenvironment,energetics,reactiveoxygenspeciesDiscoveryconsistsofseeingwhateverybodyhasseenandthinkingwhatnobodyhasthought.
AlbertSzent-GyorgyiINTRODUCTIONTheroleoflipidsinhumanhealth,nutrition,anddiseaseistakingcenterstage.
Severalcircumstancesincludinghotlydebatedissuesconcurtoexplainthisunusualinterest.
Amongthem,pressingsocietalandbiomedicalissuesconcerningtheepidemicpropor-tionsofobesityandrelateddiseasesintheUnitedStatesanditsincreasingprevalenceworldwide.
Higherfoodconsumption,declineinphysicalactivityandaprogressivelyagingpopulationareamongthesocialandbehavioralrootsofthisphenomenon.
Biologically,itadoptstheformofaso-called"metabolicsyn-drome,"asetofcomorbiditiesincludingupperbodyobesity,insulinresistance,dyslipidemia,andhypertensionthatincreasetheriskfordevelopingtype2diabetes,coronaryarterydisease,andstroke(KokandBrindley,2012;SchillingandMann,2012).
Functionalimpairmentsassociatedwithincreasedcirculat-inglevelsoflipidsandtheirinducedmetabolicalterationsinfattyacids(FAs)utilizationandintracellularsignaling,havebeenbroadlytermedlipotoxicity(Wendeetal.
,2012).
Currentscien-ticdebatesconcerntheassociationoflipotoxicitywiththeonsetofinsulinresistanceinskeletalmuscle,andwithheartdysfunctioninobeseanddiabeticpatients.
Mitochondrialfunctioniscloselyassociatedwiththemount-ingattentiononlipids.
Oneobviousreasonisthatmitochondriaarethemainsiteoflipiddegradation.
However,themajordrivingforceunderlyingthisassociationisthefundamentalroleplayedbymitochondrialdysfunctioninagingandacuteorchronicdiseaseconditionssuchasmetabolicdisorders(obesity,diabetes),cancer,inammatorydisorders,neurodegeneration,andcardiovasculardisease(Akaretal.
,2005;Aonetal.
,2009;BuggerandAbel,2010;Camaraetal.
,2011;Martinez-Outschoornetal.
,2012;Wallace,2012;Helgueraetal.
,2013;Cortassaetal.
,2014;RossignolandFrye,2014).
Cellsprotectthemselvesfromlipotoxicityordeath(Bernardietal.
,2002;Penzoetal.
,2002)byeitheroxidizingFAsorseques-teringthemastriacylglycerol(TAG)withinlipiddroplets(LDs)(Greenbergetal.
,2011;WaltherandFarese,2012)(Figure1).
TheabilitytostoreTAGinLDsisevolutionarilyconservedandobservedinyeast,plants,invertebrates,andvertebrateswww.
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MitochondrialfunctionandlipidexcessFIGURE1|Triglyceridesynthesis,storageinlipiddroplets,andFAoxidationincardiomyocytemitochondria.
AdetailedexplanationoftheprocessesdepictedinthisgurewillbefoundinsectionsLipidDropletsandTAGMetabolismandFattyAcidsandMitochondrialFunctionofthemaintext.
LDscanbeintercalatedwithmitochondriaorsurroundedbythemasshownschematicallyattherightbottom.
WhenmitochondriaandLDinteractinclosecontacttheschemesuggeststhatFAdegradationandactivationoccuratthecontactsitesbetweenbothorganelles.
FAprecursorsofβ-oxidationwillbesubsequentlymetabolicallychanneledtothematrix,andlikelyβ-oxidation,throughknownpathways(seeSectionMetabolicChannelingofLipidUtilizationFromCloseContactsBetweenMitochondriaandLipidDroplets:AHypothetical-QualitativeModelinthetextformoredetails).
(WaltherandFarese,2012).
LDsconstituteahighlydynamicFAstoragepoolthatcanbeusedforenergyreserve.
RecentevidenceshowsthatacuteexercisecantriggerchangesinthedynamicsofLDassembly,morphology,localizationandmobilizationinskele-talmuscle,aprocessregulatedbyabroadgeneticprogramaffect-ingthespatialandmetabolicinteractionbetweenmitochondriaandLDs.
Inthisprocess,theexercise-responsivetranscriptionalcoactivatorPGC-1αappearstoplayakeyroleincoordinatingintramuscularLDprogrammingwithmitochondrialremodeling(Kovesetal.
,2013).
Thereisabundantanecdotalevidencedescribingcloseinterac-tionbetweenmitochondriaandLD.
Earlyobservationsindicatedthatmitochondriaareoftenlocatednearasupplyofsubstrate,oratsitesinthecellknowntorequiretheATPgeneratedbythemitochondrion(Lehninger,1965).
OccasionalcloseassociationsbetweenmitochondriaandLDswerefoundinavarietyoftis-suessuchasmyocardium,liver,pancreas,andbrownadipose.
AsdescribedbyGhadially(1997):".
.
.
Asinglemitochondrionmayappearcloseto,spreadoutover,orfusedtothesurfaceofasmallLD,orseveralmitochondriamaybeseensurroundingalargerLD.
Inotherinstances,theLDmaylieinadeepinvaginationofthemitochondrialenvelope,anditisclearthatinanotherplaneofsectioningsuchadropletcouldeasilybemistakenforalipidinclusioninthemitochondrion.
.
.
,particularlyiftheinvaginatingmembranesarenotvisualized.
"Asearlyas1958,PaladeandSchidlowskisuggestedthatthesecloseassociationsweremeaningfulbecausethey"bringthemitochon-drialenzymesintoclosecontactwiththelipidicsubstrate"(PaladeandSchidlowski,1958,quotedbyGhadially,1997).
Althoughpotentialartifactsfromsamplepreparationcannotberuledout,andthatpathologicallyalteredmitochondriacanhaveaninuence,whendescribinglipidicinclusionsinmitochondria,Ghadially(1997)wrote:".
.
.
lipidicinclusionswerenotedinnormal-lookingmitochon-driawithwell-formedcristae,wherepresumablythelipidhasaphysiologicalrole.
"MorerecentexperimentaldataputsonamoresolidgroundtheideathattherearebothphysicalandmetabolicinteractionsbetweenLDandmitochondria.
TheseinteractionsappeartobeFrontiersinPhysiology|MitochondrialResearchJuly2014|Volume5|Article282|2Aonetal.
Mitochondrialfunctionandlipidexcessmodulatedbyrelevantphysiologicalsituationssuchasfastingandexercisetraining.
AvailableevidencealsoshowsthatproteinslocatedintheLDsurfacecloselyinteractwithenzymesofthelypolyticcascademodulatingFAacidefuxfromthedroplet.
LIPIDDROPLETSANDTAGMETABOLISMTAGisthemajorformofenergystoragethatwithsterolestersserveasreservoirsofmembranelipidcomponents(WaltherandFarese,2009).
IncardiomyocytesTAGsaresynthesizedbyacyltransferasesandphosphatasesatthesarcoplasmicreticu-lumandmitochondrialmembraneandthenpackagedintoLDs(WaltherandFarese,2009;SinghandCuervo,2012;Kienesbergeretal.
,2013).
TAGsynthesisisinitiatedbyglycerol-3-phosphateacyltransferases(GPAT)atthemitochondrialandsarcoplas-micreticulummembraneandthencompletedatthesarcoplas-micreticulumbysn-1-acyl-glycerol-3-phosphateacyltransferase(AGPAT),phosphatidicacidphosphatase(PAP),andsn-1,2-diacylglycerolacyltransferase(DGAT)reactions(Kienesbergeretal.
,2013)(Figure1).
NewlyformedTAGsarepackagedintocytoplasmicLDs.
Thus,lipidsarenotstoredasFAsbutasTAGs(triglycerides)producedbyaseriesofestericationreactionsthatcombinethreeFAmoleculeswithglycerol3-phosphate;forexample,theTAGforpalmitateistripalmitin.
LDsareconsidereddynamiccellularorganellesratherthansimplelipidstoragedepotsthat,relativelyrecently,havebeenimplicatedinmanybiologicalprocesses(WaltherandFarese,2009,2012;GreenbergandColeman,2011;SinghandCuervo,2012).
LDssizevariesfromadiameterof0.
1μminyeasttoover100μminawhiteadipocyte.
LDsconsistofasingleprotein-decoratedphospholipidmonolayerthatdelimitstheirhydropho-biccorefromtherestofthecell(FujimotoandParton,2011).
Thehydrophobiccorecontainsneutrallipids,mostnotablyTAGandsterolesters.
TheadiposetissueLDhasacorepredominantlyformedbyTAGwhereasinmostcellscholesterolandTAGsharethenuclearcoreoftheLD(SinghandCuervo,2012).
LDsareprominentinmanytypesofmammaliancells,withadipocytesbeingthemosthighlyspecializedforlipidandenergystorage.
LDsinteractwiththeendoplasmicreticulumandthemitochondria—thetwoorganellesthathavebeenproposedassitesofformationoftheautophagosomelimitingmembrane(Fujimotoetal.
,2008;Murphyetal.
,2009;SinghandCuervo,2012).
SuchcontactzonesarealsositesofactivelipidsynthesisenrichedinAcylCoA:diacylglycerolacyltransferase2(DGAT2),themajorenzymecatalyzingTAGsynthesis(Casesetal.
,2001;WaltherandFarese,2009).
TAGstoredinLDsiscatabolizedbythesequentialhydroly-sisofesterbondsbetweenFAsandtheglycerolbackbone.
TAGhydrolysisisatightlyregulatedprocessthatinvolvesacomplexinteractionbetweenlipasesandregulatoryproteins(Lassetal.
,2011).
TAGcatabolismisperformedbyacascadeoflipolyticreactionsthatisinitiatedbyadiposetriglyceridelipase(ATGL)producingdiacylglycerol(DAG).
Hormone-sensitivelipase(HSL)andmonoacylglycerollipase(MGL)completethelipolyticcas-cadebysequentiallyhydrolyzingDAGandmonoacylglycerol(MAG),respectively,(Figure1).
MAGlipase(MGL)performsthenalstepinTAGcatabolismbyhydrolyzingMAGstoglycerolandFAs(Kienesbergeretal.
,2013).
TherateoflipolysiscanbedramaticallystimulatedbyadrenergichormonesviaactivationofproteinkinaseA(PKA).
PKAphosphorylatesperilipinandHSLandcausesacomplexsetofeventsleadingtoTAGhydrolysis.
TheFAsreleasedduringTAGcatabolismaremainlyusedforβ-oxidationandsubsequentATPsynthesisviaOxPhosinmito-chondria(Figure1;seebelow:FattyAcidsandMitochondrialFunction).
Inoxidativetissuessuchastheheart,TAG-derivedFAsareutilizedasanenergysource,buttheyalsoserveassignalingmoleculesaswellasbuildingblocksformembranesandcomplexlipids.
Hepatocytes,heartandskeletalmyocytes,adrenocorticalcells,enterocytes,andmacrophagesmayallcontainlargeamountsofLDs.
ExcessiveLDaccumulationisahallmarkofT2DM,obesity,atherosclerosis,hepaticsteatosis,andothermetabolicdiseases.
However,incertainorganslikeskeletalmuscle,intramy-ocellulartriacylglycerol(IMTG)accumulationisnotstrictlyapathologicphenomenon(seebelow:Mitochondria,LipidsandInsulinResistance).
Lipidcontentiselevatedinredcomparedwithwhiteskeletalmusclesandincreasesinresponsetohabit-ualexerciseinbothoxidativeandglycolyticbers.
The"athleteparadox"consistsofIMTGaccumulationobservedinendurance-trainedathletesthatretaininsulinsensitivityirrespectiveofthefactthatinsomecasesIMTGsexceedthosemeasuredinseden-taryobeseorT2DMobesepatients(Goodpasteretal.
,2001;vanLoonetal.
,2003;Shawetal.
,2010;EganandZierath,2013;Kovesetal.
,2013).
Aswithaerobicexercise,bothmuscleglycogenandIMTGcontributetoenergyprovisionduringresistanceexercise(Koopmanetal.
,2006).
MITOCHONDRIAANDPERILIPINSTheproteinfamilyofperilipins(Plin)isassociatedwithLDs.
AsscaffoldingproteinsperilipinsaffectthespatialandmetabolicinteractionsbetweenLDandmitochondria(Figure1).
DevelopmentoftissuelipotoxicityanddysfunctionislinkedtoalterationsinLDbiogenesisandregulationofTAGhydrolysis(WangandSztalryd,2011).
SinceinresponsetolipidloadingofcellsperilipinsassociatewithLDstheroleoftheseproteinsisunderintensescrutiny.
ThePlinproteinfamily,orPATforperilipin/ADRP/TIP47,isconstitutedbyPlin1toPlin5,anddropletsmaycontainvariouscombinationsofthem(Greenbergetal.
,2011).
Plin1isthemostabundantPATproteininadipocytesandPlin2intheliver,whereithasbeenlinkedtohepaticsteatosis.
WhereasPlin1and4arelimitedtoadiposetissue,Plin2and3areubiquitous.
Plin1and2arealwaysfoundinanLD-boundstatewhereasPlin3to5canbeeitherLD-boundorfreeinthecytoplasm.
Geneticmanipulationsaimingatablatingperilipinstoinferabouttheirphysiologicalrolesandimpactonfatdepositionhavebeenperformed.
Plin1-nullmiceareleananddevelopsys-temicinsulinresistanceastheygrowolder.
Plin1-nulladipocytesexhibitedenhancedratesofconstitutive(unstimulated)lipol-ysisandreducedcatecholamine-stimulatedlipolysis(Tanseyetal.
,2001).
Together,thesedatasuggestedthatPlin1proteinenhancescatecholamine-stimulatedlipolysisand,importantly,thatareductioninPlin1proteinexpressionisassociatedwithincreasedconstitutivelipolysis,whichcanpromotesystemicinsulinresistance(Greenbergetal.
,2011).
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MitochondrialfunctionandlipidexcessPlin5isfoundprimarilyinoxidativetissues,e.
g.
skeletalandheartmuscles,liver(Bickeletal.
,2009).
Plin5knockoutmicelackeddetectableLDsintheheartandhadsignicantlyreducedmyocardialTAGcontent,aneffectthatwasrescuedbylipaseinhi-bition(Kuramotoetal.
,2012).
TheexcessiveTAGcatabolismexhibitedbyPlin5-decientheartswasparalleledbyincreasedFAoxidation(FAO)andenhancedROSlevelsthatledtoanage-dependentdeclineinheartfunction.
Thus,itwassuggestedthatuncontrolledlipolysisanddefectiveTAGstorageimpaircardiacfunctionthroughchronicmitochondrialFAoverload.
Plin5mayregulateLDdegradationandtheuxoflipolysis-derivedFAstomitochondriaforenergyproduction(Figure1)(Kienesbergeretal.
,2013).
Plin5overexpressionincardiacmuscleproducedarobustincreaseinLDsresultingincardiacsteatosisbutwith-outmajorconsequencesforheartfunction.
ThisdataindicatedthatPlin5playsacriticalroleindropletformationandstabiliza-tionviaitsregulatoryroleoflipolysisinvivo(Wangetal.
,2013).
Interestingly,mitochondriainhearttissuefromthePlin5overex-pressorappearedtoalwaysbedistributedintightclustersaroundLDsexhibitingasignicantincreaseinsizewithoutchangesinnumberasrevealedbymorphometricanalysis(Wangetal.
,2013).
Inskeletalmuscle,Plin5overexpressionincreasedIMCLcontentwithouthinderinginsulinmediatedglucoseuptakewhilepro-motingtheexpressionofgenesinvolvedinmitochondrialFAOandfatcatabolism(Bosmaetal.
,2013).
Inliver,down-modulationofPlin2promotesareductioninhepaticsteatosisandincreasesinsulinsensitivity,butareductioninbothPlin2andPlin3causesinsulinresistance(Greenbergetal.
,2011).
Intheheart,Plin2doesnotpromotetheinteractionofmitochondriawithLDs,butincreasedTAGaccumulationassoci-atedwithreducedpresenceofATGLinLDanddecreasedlipolysis(Wangetal.
,2011).
Astherstenzymefromthelipolyticcascade(Zimmermannetal.
,2004),theconstitutiveactivityofATGLispredominantlyresponsibleforbasallevelsoflipolysis(Greenbergetal.
,2011).
ATGLoverexpressioninacardiomyocyte-specicmannerdecreasedmyocardialTAGandlipotoxicintermediatesaccumulationintype1diabeticmice(Pulinilkunniletal.
,2013).
ThisresultedindecreasedrelianceonFAO,andpreservedcontentofrespiratorycomplexesaswellascardiacfunctionduringearlystagesofdiabetes.
Overall,thereporteddataindicatethatreducedexpressionofperilipinsmaypromotebothlipolysisandfatoxidation,result-inginreducedintracellularTAGandadiposemass.
Ontheotherhand,excessivelypolysisanddefectivelipidstoragemaypro-moteinsulinresistanceandimpairedcardiacfunctionthroughchronicmitochondrialFAoverload.
Consequently,lipidstorageandutilizationappearstobeatightlyregulatedcellularprocess.
FATTYACIDSANDMITOCHONDRIALFUNCTIONPreservationoftheintracellularredoxenvironment(RE)iscru-cialforvitalfunctionssuchasdivision,differentiation,contractileworkandsurvivalamongstothers(SchaferandBuettner,2001;Aonetal.
,2007,2009;Brownetal.
,2010;Fisher-WellmanandNeufer,2012;Jeongetal.
,2012;Lloydetal.
,2012;MuoioandNeufer,2012;AggarwalandMakielski,2013).
MitochondriaaremaindriversoftheintracellularRE(Aonetal.
,2010,2012;Stanleyetal.
,2011;Tocchettietal.
,2012;Fisher-Wellmanetal.
,2013;Kembroetal.
,2013)andtogetherwithperoxisomesconsti-tutethemainsubcellularcompartmentswherelipiddegradationoccurs.
Yet,theimpactoflipidsonmitochondrialredoxstatusandROSemission,andtheirlinkstoenergeticsarenotfullyelucidated.
FAsaremainmetabolicfuelsinheartandskeletalmuscle,andβ-oxidationrepresentstheirmaindegradationpathway.
Therateofβ-oxidationisledbydemandsinceanincreaseinworkrateandATPutilizationleadstofasteroxidativephosphorylation(OxPhos)andtricarboxylicacid(TCA)cycleactivity.
Inturn,thedecreaseinNADHandacetyl-CoA(AcCoA)levelsleadstoanincreaseoftheβ-oxidationux(Neelyetal.
,1969;Orametal.
,1973;Eatonetal.
,1996a;Eaton,2002;Lopaschuketal.
,2010).
Lipidsaresuppliedintheformofalbumin-boundFAssecretedfromadiposetissueorbycatabolismofverylowdensitylipoprotein(VLDL)complexbycoronaryvascularendotheliallipoproteinlipases(Figure1).
LongchainFA(LCFA)trans-portrequirescarrierproteinsinthesarcolemma(FATP1,fattyacidtransporterprotein1;FABP,plasmamembrane-associatedfattyacid-bindingprotein;LCFAT,long-chainfattyacidtrans-porter;OCTN2,plasmamembranesodium-dependentcarnitinetransporter;FAT/CD36,fattyacidtranslocaseCD36)andthemitochondria(CPT1,carnitinepalmitoyltransferase1;CACT,carnitine:acylcarnitinetranslocase).
Uponentryintothecell,LCFArstgetsactivatedbyform-ingthioesterswithcoenzymeA(CoA),LCFA-CoA,andiseitheroxidizedinthemitochondriaviaβ-oxidationorformsTAGbyesterication(Figure1).
SubsequentlyTAGscanbestoredintheformofLD.
Long-chainFAsareactivatedonthemitochondrialoutermembranebythelong-chainacyl-CoAsynthetasebutthemitochondrialinnermembraneisnotpermeabletotheseacyl-CoAs.
CPT1catalyzestheconversionoflong-chainacylCoAtolong-chainacylcarnitine,whichissubsequentlyshuttledintothemitochondria(Lopaschuketal.
,2010).
ControlatthelevelofCPT1activityappearstobeimportantinheartandskeletalmus-cleβ-oxidationux(AwanandSaggerson,1993;Lopaschuketal.
,1994;Zammit,1999;Eaton,2002).
AfteritsformationbyCPT1,thelong-chainacylcarnitineistranslocatedacrosstheinnermitochondrialmembranebyCACTthatinvolvestheexchangeofcarnitineforacylcarnitine.
CACThasextremelyhighactivityinmostcelltypeswithactiveβ-oxidation(RamsayandTubbs,1976;Noeletal.
,1985;Eaton,2002).
CACTisacriticalstepinthetranslocationofFAmoietiesintothemitochondria,asevidencedbythedevelopmentofcar-diomyopathiesandirregularheartbeatsinindividualswithCACTdeciencies(Lopaschuketal.
,1994,2010).
Inthematrix,acylcarnitineisconvertedbacktoacylCoAandcatabolizedviaβ-oxidation.
Theβ-oxidationofactivatedFAsoccurswithinthemitochondrialmatrixandiscatalyzedbythesequentialactionoffourenzymefamilies(acyl-CoAdehydroge-nase,enoyl-CoAhydratase,3-hydroxyacyl-CoAdehydrogenase,and3-ketoacyl-CoAthiolase),withacyl-CoAdehydrogenaseexhibitingdifferentsubstratespecicityforshort-,medium-,long-andverylong-chainacyl-CoAs(Kunauetal.
,1995;Eatonetal.
,1996a;KernerandHoppel,2000).
Theendproductofeachcycleofβ-oxidationisAcCoA,shorteningtheLCFAby2car-bons.
AcCoAthenenterstheTCAcycleforcompleteoxidationFrontiersinPhysiology|MitochondrialResearchJuly2014|Volume5|Article282|4Aonetal.
MitochondrialfunctionandlipidexcessrenderingreducingequivalentsintheformoftheelectrondonorsNADHandFADH2leadingtoATPsynthesisviaOxPhosintherespiratorychain(Figure1).
Ultimately,ATPisutilizedbythecontractilemachinerytotransducechemicalenergyintomechan-icalwork.
ROSmayalsoaffectcontractileperformanceviasignal-ingorredoxmodicationofsensitivecysteinesfrom,e.
g.
,myosinheavychain(Cantonetal.
,2011;Steinberg,2013).
Besidestheirmetabolicroleintheprovisionofenergy,long-chainfreeFAsexertdiverseeffectsoncellularmembranesandonthecatalyticactivitiesofmanyenzymes(Loskovichetal.
,2005).
FAsplaythedualroleofuncouplersandinhibitorsofmito-chondrialrespiration(WojtczakandSchonfeld,1993)throughaprotonophoriceffectontheinnermembrane,andaninhibitoryactionontheelectrontransferchain(SchonfeldandReiser,2006;SchonfeldandWojtczak,2007,2008).
Additionally,FAshavethepotentialtodrasticallyaltermitochondrialmembranesper-meabilitythroughopeningofthepermeabilitytransitionpore(Scorranoetal.
,2001;Bernardietal.
,2002;Penzoetal.
,2002,2004).
Excludedfromtheseeffectsaretheacyl-CoAsthatdonotexertprotonophoricactivityanddonotuncoupleOxPhosbecausetheyareunabletocrosstheinnermitochondrialmem-brane(Wojtczak,1976).
FreeFAscanactasspeciccomplexI-directedinhibitors(Loskovichetal.
,2005;SchonfeldandWojtczak,2008),andlong-chainacyl-CoAsareknowninhibitorsofANT(PandeandBlanchaer,1971;Lerneretal.
,1972;Wojtczak,1976).
Theinhibi-tionisofacompetitivecharacter(DuszynskiandWojtczak,1975)andstronglydependsonthecarbonchainlengthofthefattyacylmoiety(Moreletal.
,1974).
FurtherevidencethatFAs,intheiranionicform,canbesubstratesfortransportbyANTwasgivenbytheirinhibitoryeffectonATPandADPexchanges(WojtczakandZaluska,1967;Schonfeldetal.
,1996;Klingenberg,2008).
AccordingtotheFAcyclingmodel(Skulachev,1991)undissoci-atedFAmoleculescanundergoaspontaneousip-opfromtheoutertotheinnerleaetoftheinnermitochondrialmembranewheretheyreleaseprotonsbecauseofthealkalinemilieuofthematrix.
Then,intheformofanions,theyaretransportedbacktotheexternalleaetbyANT;oneprotonistransferredfromtheexternalspacetothematrixcompartmentpermoleculeoftheFApercycle.
Inthismanner,FAscanleadtoenergydissipationthroughaselectiveprotonophoricactionmediatedbycouplingoftransmembranemovementofthefattyacylanion(viatheANT,uncouplingproteins,UCPs,and/orotherinnermembranecarriers).
Theseeventsresultindissipativeprotoncyclingthatdecreasestheprotonmotiveforcetherebyaffectingrespiration,ATPsynthesis,andionhomeostasis.
PalmitoylCoAinhibitstheANTindependentlyfromβ-oxidation,accordingtomorerecentevidenceobtainedinisolatedmitochondriafromratliver(Ciapaiteetal.
,2005)andguineapigheart(AonandCortassa,unpublished)respiringonG/M.
InthecaseoflivermitochondriaitwasshownthattheANTinhi-bitioninducedchangesinintra-andextra-mitochondrialATPconcentrationsandm.
ThisinterferencewiththeANTcarrierincreasedmandthereductionlevelofcoenzymeQ(Bakkeretal.
,2000)bothexpectedtopromotetheformationofROS.
StudiesfurthershowedthatthePCoA-elicitedconcentration-dependentH2O2formationcanbeexplainedbyitseffectonmthatinthepresenceof5μMPCoAshoweda13mVincrease(Ciapaiteetal.
,2006).
ThespecicactionofPCoAontheANTintheliver(Ciapaiteetal.
,2006),isincontrastwithanapparentmultitargeteffectintheheart(AonandCortassa,unpublished).
Thesedifferencesmaybegivenbyintrinsicfunctionaldifferencesduetospecies(rat,guineapig)ororganspecicity,e.
g.
,liverandheartmitochondria.
DifferencesmayalsobelinkedtothepresenceofdistinctFAtransporters(FATPsorSLC27As)orFAbindingproteins(FABPs).
MITOCHONDRIA,LIPIDS,ANDINSULINRESISTANCETheshiftfromintermediatevaluesofRE,correspondingtoROSlevelscompatiblewithsignalingfunctions(Aonetal.
,2010;Cortassaetal.
,2014),towardeithermorereducingoroxidizingconditionsisatopicofgreatpotentialimportanceandinterestwithimplicationsforinsulinsignaling.
Indeed,theassociationbetweenlipotoxicityandtheonsetofinsulinresistanceinskele-talmuscleisahotlydebatedsubject(MuoioandNeufer,2012).
OnesidepositsthatitisduetodysfunctionalmitochondriawithintrinsicdecienciesinOxPhosanddecitsinfatoxidation.
TheseimpairmentsimpingeoninsulinsignalingbydivertingFAsawayfromoxidationandtowardproductionofDAGs,ceramideandothertoxiclipidspecies(LowellandShulman,2005;Roden,2005).
Theothersideofthedebatenotesthatthisideaisincom-patiblewiththeprinciplesofbioenergeticsbecausemitochondrialrespirationisgovernedbyenergydemand;intracellularlipidswillaccumulatewheneverFAssupplyexceedstheenergyneedsofthecell.
Consequently,theysuggestthattheetiologyofmuscleinsulinresistanceisgroundedonthefundamentalprinciplesthatgov-erncellularandmitochondrialbioenergeticsandtheredoxstressthatisplacedontherespiratorysystemwhenenergysupplyper-sistentlyoutpacesenergydemand(MuoioandNeufer,2012).
InagreementwiththisideaotherauthorshaveemphasizedthatthematchingbetweenincreasedFAavailabilityandoxidativecapacitydistinguishestheincreaseinIMTGfollowingendurancetrainingfromobesity/diabeticconditions.
Chronicexercisetrainingcanelicithighoxidativecapacityconferredbyhighermitochondrialcontentbutnotmitochondrialfunction.
Undertheseconditions,lipidinfusioninendurance-trainedathletesisabletoreduceinsulinsensitivityonlyby29%ascomparedto63%inuntrainedsubjects(Phielixetal.
,2012).
WhereasinexercisetrainingIMTGreectsanincreasedrelianceonfatsassubstrate,inobesity/diabeteswillimplyaccumulationoflipidmetabolites[longchainfattyacyl-CoA(LCFA-CoA),DAG,andceramide]thatareresponsiblefortheimpairmentininsulinactionratherthantheIMTGpoolcon-tainedinLDs(Schrauwenetal.
,2010;Fisher-WellmanandNeufer,2012).
Apparently,increasedconcentrationsofintramus-cularLCFA-CoAandDAGactivatePKC,whichappearstoinduceimpairmentsininsulinsignalingviaserinephosphorylationoftheinsulinreceptorsubstrate-1.
Inamodelofdiet-inducedobe-sity,accumulationofacylcarnitines,asproductsofincompleteβ-oxidation,wasshowninskeletalmuscle(Kovesetal.
,2008).
Thesendingsledtotheideaofamitochondria-derivedsig-nalthatcouplesincompleteβ-oxidationwithinsulinresistance.
ChronicelevationsofincompleteoxidationintermediatesofFAsandbranched-chainaminoacids(Newgard,2012)mightfosterwww.
frontiersin.
orgJuly2014|Volume5|Article282|5Aonetal.
MitochondrialfunctionandlipidexcessamitochondrialmicroenvironmentthatisconducivetohigherH2O2releasefrommitochondriawithpotentialtomodulateinsulinsignaling(Fisher-WellmanandNeufer,2012;MuoioandNeufer,2012).
Thedebateabouttheroleofmitochondrialandlipidmetabolismattheoriginofinsulinresistanceishighlyrelevantforthediabeticheartbecauseofitsheavydependenceonfatsforfunction(Hollowayetal.
,2009,2011).
Thedebatecenteredonthemitochondrialload-oxidativepotentialinskeletalmuscle,isalsorelevantfortheheartwherefunctionisledbyenergydemand.
Infact,lipidaccumulationintheheartislargelyseenasamis-matchbetweensupplyanddemand,i.
e.
,lipidsamasswhensupplyoutpacesdemand.
Afundamentallyimportantquestionstillheavilydebatediswhetherornotashiftinsubstratepreferencetowardfatoxi-dationlowersdiseaserisk(MuoioandNeufer,2012).
FAsandglucosearethetwomajorfuelsdrivingheartcontraction.
Intype2diabetesandobesityFAOisincreased(Lopaschuk,2002;CarleyandSeverson,2005)butourknowledgeaboutthecom-binedeffectsofhyperglycemia,ahallmarkofdiabetes,andhighFAavailability,onmetabolism,redox/ROSbalanceandtheirimpactonheartfunctionisincomplete.
Althoughthehealthyheartisexibleregardingfuelselection,inthemetabolicallychallengeddiabeticheartbyhighlevelsofglucoseandfat,thefactorscontributingtodysfunctionandwhicharebenecialasenergysourceorredoxdonorsarestillunclear.
Existingcom-pellingevidenceindicatesthatsubstrate-drivenredoxstatusplaysacriticalroleincardiaccontractileperformanceintype2diabeteswherecellular/mitochondrialredoxandenergeticsarealtered(seebelow:Mitochondrial,CellularandOrganMechanismsforManagingLipidAfuence)(Andersonetal.
,2009a;Tocchettietal.
,2012).
Overall,thereisnodisputingthatlipidoxidationcon-fersametabolicadvantageduringstarvationandexercise,buttheroleoffuelselectionperseindefendingagainstmetabolicdiseaseneedsfurtherinvestigation.
MITOCHONDRIAL,CELLULAR,ANDORGANMECHANISMSFORMANAGINGLIPIDAFFLUENCEAsimportantfuelsofcellularfunctionitisverywellknownhowFAsaredegradedbymitochondria.
Yet,themechanismsbywhichmitochondriamanagelipidexcessarelargelyunknown.
Theroleofβ-oxidationperseasanunderlyingcauseofobesity-associatedglucoseintoleranceremainsatopicofactiveresearchanddebate(Fisher-WellmanandNeufer,2012;MuoioandNeufer,2012).
Furthermore,mitochondriaplayacentralroleinthedevelop-mentofdiabetesandobesitycomplications(BuggerandAbel,2010;SivitzandYorek,2010)andtheirenergetic/redoxdysfunc-tionisdirectlyinvolvedintheredoximbalanceexhibitedbytheheart(Tocchettietal.
,2012;Frasieretal.
,2013)andskeletalmuscle(Andersonetal.
,2009a).
MitochondriaandlipidoxidationplayapredominantroleasdriversoftheintracellularRE.
FAsareamajorsourceofcellu-larATPwhich,intheheart,issynthesizeduptotwothirdsviareducingequivalents(e.
g.
,24NADH,8FADH2forpalmitate)derivedfromβ-oxidationinmitochondria.
ThehigherenergeticbudgetprovidedbythesaturatedFApalmitate(threetimeshigherthanfromglucosewhenATP/molsubstrateisconsidered)intheformofreducingpowerprovideselectronstoantioxidantsys-temsandthemitochondriarespiratory/energeticmachinery.
Inagreementwiththeprominentroleoflipidsontheintracellu-larredoxstatus,itwasshownthatPalmdeterminedatransitionfromoxidized-to-reducedcellularredoxstatusincardiomyocytesfromtype-2diabetic(db/db)heartsabatingROSlevelsdrasti-cally(Tocchettietal.
,2012).
ThiseffectwascoupledtoamarkedGSHrisebothinwildtypeanddb/dbmyocytes.
Asaconse-quenceofitsfavorableeffectoncellularredoxbalance,Palmsignicantlyimprovedisoproterenol-inducedcontractilereserveindb/dbcardiomyocytes(Tocchettietal.
,2012).
Keepingapropercellular/mitochondrialREisvitalforoptimalexcitation-contraction(EC)couplingaswellasenergysupplyintheheart(Burgoyneetal.
,2012;ChristiansandBenjamin,2012;Nickeletal.
,2013,2014).
IntracellularredoxbalanceaffectsCa2+handlingbyinterferingwithawiderangeofproteinsimplicatedinECcoupling(Fauconnieretal.
,2007)includingtheSRCa2+releasechannels[theryanodinereceptors],theSRCa2+pumps,andthesarcolemmalNa+/Ca2+exchanger(ZimaandBlatter,2006;DedkovaandBlatter,2008).
Alsounknowniswhetherthemechanismsutilizedbymitochondriatodealwithlipidexcessdifferbetweenorgans.
Importantexamplesaretheskeletalandcardiacmuscleswhereβ-oxidationpredominatesduetotheirlackofdenovolipogenesis(Eaton,2002).
Certainly,theorgan'sfunc-tionalspecicityplaysarole.
Asamatteroffact,skeletalmuscleisthelargestglycogenstorageorgan(4-foldthecapacityoftheliver)thuscriticalforglycemiccontrolasthepredominant(80%)siteofglucosedisposalunderinsulin-stimulatedcon-ditions(DeFronzoetal.
,1981;EganandZierath,2013).
Ontheotherhand,theheartcarriesoutitspumpfunctiontransducingthechemicalenergystoredinFAsandglucoseintomechani-calandelectricalenergy.
Atrest,theheartcyclesabout6kgofATPeverydaywhilebeatingabout100,000times(Neubauer,2007).
MitochondriaprovidethebulkoftheATPneededforcardiacmusclecontraction(abouttwothirds)andsarcolemmalandsarcoplasmiciontransport(onethird),responsiblefortheCa2+transientsandelectricalactivityincardiaccells(SolainiandHarris,2005;Cortassaetal.
,2009;Nickeletal.
,2013).
ThefarhigheramountsofO2processedbytheheartonaspecicbasiswithrespectto,e.
g.
,brainandskeletalmuscle(RolfeandBrown,1997),anditscontinuousactivity,makethisorgansusceptibletooxidativedamage(Burgoyneetal.
,2012;ChristiansandBenjamin,2012).
Asamatteroffact,myocardialfunctionandtheabilityofthehearttotoleratestressdeclinewithage(LakattaandSollott,2002).
Althoughthemechanismscon-tributingtoage-relatedalterationsinmyocardialfunctionarenotfullyunderstood,mitochondrialdysfunction,oxidativestressandtheaccumulationofoxidant-induceddamagearemajorfactors(Fanninetal.
,1999;Suhetal.
,2003;Judgeetal.
,2005).
DefectsinmitochondrialFAβ-oxidationleadtoseveralwell-knownmetabolicdisorders,suchasReyesyndrome,cardiomy-opathyandsuddeninfantdeathsyndrome(RoeandDing,2001;Yangetal.
,2001).
Themaintenanceofhighlevelsofmitochon-drialβ-oxidationcouldreducetheexcessivefataccumulationandstorageleadingtohumanobesity.
LipidoverloadinvolvingTAGaccumulationinnon-adiposetissuescharacterizesdisorderssuchashyperlipidemiaandlipodystrophies,heartdysfunction,liverFrontiersinPhysiology|MitochondrialResearchJuly2014|Volume5|Article282|6Aonetal.
Mitochondrialfunctionandlipidexcessdisease,inbothhumansandinanimalmodelsofobesityanddiabetes.
ItisbecomingincreasinglyclearthatadequateregulationofTAGmetabolismindifferentorgansiscriticalforbothenergymetabolismandfunction.
Liverandheartrespondtothemas-siveinuxoflipidsfrombloodbyupregulatingLDbiogenesis,asamechanismofdefenseagainstthetoxicityofFAs,whichuponestericationgetconvertedintoTAGandstoredintoLD(Lassetal.
,2011).
Failuretodosointheliveroriginatespathogenicconditionssuchassteatosisandsteatohepatitis(Greenbergetal.
,2011).
ThelipidexcesssituationisalsorelevantforheartfunctioninT2DMwhereFAsarepreferredfuels(Lopaschuketal.
,2010).
However,underacute,non-chronic,conditionsFAscanexhibitadvantageousactions,especiallyintheheartunderdiabeticcon-ditions(Tocchettietal.
,2012).
CellularTAGaccumulationinLDsmaybebenecialratherthandetrimentalbecauseitdivertsFAsfrompathwaysleadingtocytotoxicitythusservingasabufferagainstlipotoxicity(Listenbergeretal.
,2003).
Fromtheexamplesandargumentsabove,itisclearthatlipidshaveaconsiderableimpactonmanycellularprocesses,includ-ingmitochondria.
Thisimpactinuencesthefunctionaloutcomeofseveralorganssuchastheliver,skeletalandcardiacmuscles.
Deregulationoflipidmetabolismproducesoverloadthatisattheoriginorasanaggravatingconsequenceofmanydiseases.
Consequently,thefundamentalaswellaspracticalimportanceofunravelingthemechanismsbywhichmitochondriahandlelipidsexcesscannotbeoverstated.
First,atthemostbasiclevel,wedonotknowenoughaboutlipidsactiononmitochondrialener-geticandredoxfunctions.
LipidscanactbothasuncouplersandinhibitorsofOxPhos(WojtczakandSchonfeld,1993;Bernardietal.
,2002),andtheconsequencesofthesecontradictoryeffectsonmitochondrialenergetic,redoxandsignalingfunctionsarejuststartingtobeunraveled(SchonfeldandWojtczak,2008).
Second,besidesbeingthemainsiteoflipiddegradation,mitochondriamaybeactivelymodulatingthebalancebetweenlipidstorageandutilization.
Inthefollowingsectionsweexploresomeofthenewemergingmechanismsoflipidstorageandutilizationbymitochondriaattheorganelle,cellularandorganlevelindifferentphysiologicalsettings.
CLOSECONTACTMITOCHONDRIA-LIPIDDROPLETRegularexerciseandphysicalactivityareconsideredcornerstonesintheprevention,management,andtreatmentofnumerouschronicconditions,includinghypertension,coronaryheartdis-ease,obesity,T2DM,andage-relatedmusclewasting(sarcopenia)(Haskelletal.
,2007;Colbergetal.
,2010;EganandZierath,2013).
Exercisetrainingenhancesmitochondrialbiogenesisandper-formanceinskeletalmuscle(Irrcheretal.
,2003),butnotintheheart(Lietal.
,2011).
WhetherthesameistrueinT2DMheartsisunclear.
InelectronmicrographsLDscanbeeasilydetectedintype2diabetic(db/db)(Boudinaetal.
,2007)orob/ob(Geetal.
,2012)butnotinWTmicehearts.
IncellsLDscanbereadilyvisu-alizedusingtheuorescentFAanalog(dodecanoicacid)BODIPYthatlabelsneutrallipidsincytoplasmicdroplets(WaltherandFarese,2012).
TheoccurrenceofclosecontactbetweenmitochondriaandLDintheheartisremarkablebecauseofitsdependenceonmito-chondrialenergeticspreferentiallyfueledbyFAs.
Morenotewor-thythoughisthefactthattheseclosecontactsoccurintheT2DMheart,wherethedependenceonfatfuelingisevenmorepromi-nent(Lopaschuk,2002;BuggerandAbel,2010).
Interestingly,Plin5overexpressioninhearttissuerenderedtightmitochondrialclustersaroundLDswithmitochondriasignicantlylargerbutnothigherinnumber(Wangetal.
,2013).
Thesameauthorspro-posedthatPlin5couldplayaregulatoryroleintheFAuxfromLDstomitochondriaunderconditionsofincreasedcellularFAinux(WangandSztalryd,2011).
ThesedataalsosuggestthatPlin5withitsroleoffavoringLDaccumulationmayacttokeeptheintracellularlevelsofFAmetabolites(e.
g.
,DAG,ceramide)belowlipotoxicamounts(seebelow:MetabolicChannelingofLipidUtilizationFromCloseContactsBetweenMitochondriaandLipidDroplets:AHypothetical-QualitativeModel).
InskeletalmuscleIMTGaccumulatesandisactivelyutilizedduringexercise(Shawetal.
,2010;EganandZierath,2013;Kovesetal.
,2013).
Enduranceexercisetrainingincreasesmitochon-drialcontent(bysizenotnumbers)formenandwomenbuthealthyactivewomenhavehigherIMTGaccumulationcom-paredwithmenduetogreaternumberratherthansizeofLDs(Tarnopolskyetal.
,2007).
Interestingly,thisstudyalsoreportedanincreaseinthephysicalcontactbetweenmitochondriaandIMTGsfollowingenduranceexercisetraining.
RatesofwholebodyfatoxidationandIMTGutilizationaredeterminedbyfac-torssuchasdiet,intensityanddurationofexercise,andtness.
Duringacuteexercise,thecontributionofvariousmetabolicpathwaystoenergyprovisionisdeterminedbytherelativeinten-sityandabsolutepoweroutputoftheexercisebout(EganandZierath,2013).
TherateofATPdemandandenergyexpendi-tureisdeterminedbytheabsolutepoweroutputwhereastherelativeexerciseintensityinuencestherelativecontributionsofcarbohydrateoxidationandlipidsources,andcirculating(extra-muscular)andintramuscularfuelstores,toenergyprovision.
Asexerciseintensityincreases,muscleutilizationofcirculatingfreeFAsslightlydeclines,whereasutilizationofcirculatingglucoseincreasesprogressivelyuptonear-maximalintensities(vanLoonetal.
,2001).
IMTGbreakdownoccursprimarilyviaHSLandATGL(WattandSpriet,2010).
AlthoughIMTGsconstituteonlyasmallfraction(1–2%)ofwhole-bodylipidstorestheyrepresentanimportantfuelsourceduringprolonged(>90min)butmoder-ateintensityexercise.
IMTGscanprovide25%oftotalenergyhowevertheircontributiondecreasesateitherhigherorlowerintensitiesofexercise(Romijnetal.
,1993;vanLoonetal.
,2001).
Maximalratesoffatoxidationoccuratmoderateexer-ciseintensities(60%VO2max)(Shawetal.
,2010;EganandZierath,2013).
Atlow-to-moderateexerciseintensity,thepri-marysubstratesfuelingskeletalmuscleareglucose,derivedfromhepaticglycogenolysis(orgluconeogenesis)ororalingestion,andfreeFAsreleasedbyadiposetissuelipolysis.
Prolongedexercise(>60min)ataxedintensityincreasestheenergycontributionfromlipidoxidation(EganandZierath,2013).
IMTGstorescanbereducedby60%followingexercise,pre-dominantlyintypeImusclebers(vanLoonetal.
,2003;www.
frontiersin.
orgJuly2014|Volume5|Article282|7Aonetal.
MitochondrialfunctionandlipidexcessStellingwerffetal.
,2007;Shawetal.
,2010;EganandZierath,2013).
Lipophagy,i.
e.
,theturnoverofLDsbyautophagy,mayoccurduetorandomsequestrationofcytosolicmaterialby"inbulk"autophagy.
However,whenlipophagyisactivatedinresponsetoalipidchallengeorprolongedstarvation,aswitchtowardthepref-erentialsequestrationofLDseemstohappen,supportingsomelevelofselectivityinthisprocess(Singhetal.
,2009).
Wesuggestthatthismayalsobethecaseforclosecontactsmitochondria-LD,andthatenergydemandmaybeamainelicitoroftheinterac-tionbetweenthesetwoorganelles.
Consonantwiththisidea,ithasbeenproposedthatLDsassemblyinskeletalmuscleunderexercisetrainingwouldimprovethemanagementofhighFAinuxenablingamorepreciselyregulatedtrafckingofsubstratetoandfromIMTGthuscontributingtooptimalmitochondrialperformanceandmetabolicexibility(Kovesetal.
,2013).
LIPOTOXICITYANDLDACCUMULATIONDYNAMICSInpathologicstateslipotoxicitymayoccurovertime,despiteTAGaccumulation,wheneitherthecellularcapacityforTAGstorageisexceededorwhentriglyceridepoolsarehydrolyzed,resultinginincreasedcellularfreeFAlevels.
Thus,thedurationandextentoflipidoverloadmaydetermineifacellisprotectedordamaged.
Whethermitochondrialenergy/redoxstatuscanalterthebalanceLDformationandutilizationintheshort-termisaquestionthathasnotbeenhithertoaddressed.
Studiesperformedwithnon-invasivespectroscopictechniqueshaveshownelevatedIMCLtriglyceridecontentintheleftventri-cle(i.
e.
,LVsteatosis)ofobeseandT2DMpatients(McGavocketal.
,2007;Rijzewijketal.
,2008)butitsassociationwithearlydiastolicdysfunctionleadingtosubsequentsystolicdysfunctionremainscontroversial(Andersonetal.
,2009b;Lopaschuketal.
,2010).
Again,lipidsthroughaccumulationoftriglyceridesareatthecenterofthecontroversy.
Inskeletal(Liuetal.
,2007)andcar-diac(Ussheretal.
,2009)muscle,IMCLaccumulationasaresultofdiet-inducedobesityisnotatallpathogenic,butmayevenbeprotectiveagainstobesity-associatedmaladies.
PreviousreportshavelinkedROS-mediatedmitochondrialdysfunctiontoDAGandceramide,twomainproductsoflipiddegradation(CoenandGoodpaster,2012).
Lipidchannelingtomitochondriamayrepresentamechanismbywhichconcentra-tionbuild-upoftheseintermediariesisavoided,especiallyunderhighenergydemand.
Basedonthesepremises,wesuggestthattemporarylipidstorageinLDsdoesnotnecessarilyrepresentpathophysiologicalbehavior.
Onthecontrary,itmayembodyanadaptiveresponse,atleastintheshort-termthusrepresentinganadaptivestrategyoflipidsutilizationensuringenergysup-plywithoutaffectingneithermitochondrialnorcellularredoxstatus.
REDOXOPTIMIZEDROSBALANCEANDMITOCHONDRIALREDOXANDENERGETICSLipidmetabolitescandamagetherespiratorychainleadingtoimpairedenergetictransitioninmitochondriathroughtheirdualeffectasuncouplersandinhibitors(WojtczakandSchonfeld,1993).
Impairmentofthekeystate4→3energetictransitioncanoccurviainhibitionofANTorATPsynthasetherebyproducingacontinuousreleaseofROSirrespectiveofADPaddition(Tocchettietal.
,2012).
MitochondriaareamainsourceofROSbutcanalsobetheirtarget.
TheREisamajordrivingforceofthecrucialenergy-redoxlinkofmitochondrialfunction(Cortassaetal.
,2014).
ThemitochondrialREdependsontheintrinsicredoxpotentialandinstantaneousreducingcapacityofthisorganelleaswellasitsresponsetothecytoplasmicredoxstatus(Aonetal.
,2010;Kembroetal.
,2013).
Inthiscontext,Redox-OptimizedROSBalance(R-ORB)providesausefulconceptualframeworktorationalizemanyresultsdescribedinthepresentreview.
OneofthemainR-ORBpostulatesisthatROSefuxfrommitochon-driawillattainaminimumatintermediatevaluesofRE,whenVO2reachesamaximumfollowingADPstimulation(Figure2)(Cortassaetal.
,2014).
Understate3respiration,glutathioneandthioredoxinsystemsareessentialforminimizingROSreleasefrommitochondria(Aonetal.
,2010,2012;Stanleyetal.
,2011;Kudinetal.
,2012;Cortassaetal.
,2014).
Inexcess,lipidprecur-sorsofβ-oxidationcanpromotemitochondrialuncouplingandoxidizedredoxstatus(AonandCortassa,unpublished).
InmoreoxidizedRE,awayfromtheoptimum(intermediate)REcompati-blewithminimalROS,antioxidantsystemsbecomeoverwhelmedleadingtopathologicalROSoverow(Aonetal.
,2010;Cortassaetal.
,2014).
Mitochondriafunctioninmoreoxidativeenvironmentsinchronicdiseases(Tocchettietal.
,2012).
Thus,itbecomesfunda-mentaltounderstandhowoxidativestressinuencesthedepen-denceofROSemissiononrespiration(Cortassaetal.
,2014).
Whenoxidantchallenged,mitochondriadisplayedH2O2emis-sionlevels2-foldhigherthancontrols,andexhibitedlowerres-piration(Figure2).
OxidativestressshiftedredoxbalancetowardthemoreoxidizedrangewherethesensitivityoftheROSefuxtotheREdecreasesmoredrasticallyinstate4thaninstate3respiration.
A50%decreaseinreducedglutathione(GSH)wasmainlyresponsiblefortheshiftoftheREtoamoreoxidizedstate(Cortassaetal.
,2014).
METABOLICCHANNELINGOFLIPIDUTILIZATIONFROMCLOSECONTACTSBETWEENMITOCHONDRIAANDLIPIDDROPLETS:AHYPOTHETICAL-QUALITATIVEMODELRecentevidencesupportsphysicalandmetabolicinteractionsbetweenLDsandmitochondriamediatedbythescaffoldingproteinPlin5(WangandSztalryd,2011;Wangetal.
,2011;Kovesetal.
,2013).
WangandcollaboratorsobservedthatPlin5-overexpressingcellsshowdecreasedLDhydrolysisandpalmitateβ-oxidationwhencomparedwithcontrols.
Instead,palmitateincreasinglyincorporatedintoTAGsunderbasalconditionswhereasinproteinkinaseA-stimulatedstateLDhydrolysisinhibi-tionwasremovedandFAsreleasedforβ-oxidation.
TheseresultssuggestedthatPlin5regulatesLDhydrolysisandcontrolslocalFAuxtoprotectmitochondriaagainstexcessiveexposuretoFA(WangandSztalryd,2011).
Alltheseobservationsareinagree-mentwiththerelativelyrecentrealizationthattheLDproteomeishighlydynamicandmorecomplexthanpreviouslythought.
TheLDproteomecontainskeycomponentsofthefatmobilizationsystemandproteinsthatsuggestLDinteractionswithavarietyofcellorganelles,includingthemitochondria(Belleretal.
,2010).
FrontiersinPhysiology|MitochondrialResearchJuly2014|Volume5|Article282|8Aonetal.
MitochondrialfunctionandlipidexcessFIGURE2|Redox-OptimizedROSBalanceandtheeffectofoxidativestressonmitochondrialrespiration,H2O2emission,andtheRE.
R-ORBpostulatesthatROSlevels(asthenetresultofproductionandscavenging)dependontheintra-cellularand-mitochondrialredoxenvironment(RE).
ItalsoproposesthatthereisaminimumlevelofROSemissionwhenmitochondriamaximizetheirenergeticoutput.
Underhighenergydemand,anddespitelargerespiratoryrates,ROSemissionlevelswillbekepttoaminimumbyROSscavengingsystems(Stanleyetal.
,2011;Aonetal.
,2012).
OxidativestresscanhappenateitherextremeofRE,eitherhighlyreducedorhighlyoxidized,butgovernedbydifferentmechanisms(Aonetal.
,2010;Kembroetal.
,2014).
Theplotdisplaysschematicallythesummaryoftheresponseofrespiration(blacktraces)andROSemissioninstressedmitochondria(graytraces)plusfurtheradditionoftheuncouplerFCCP(dashed-dottedline).
Continuouslinescorrespondtotheabsenceofstresswhereasdashedlinesbelongtomitochondriaunderstressedconditions(Cortassaetal.
,2014).
BlackarrowsindicatethedirectionofchangeinVO2andROSelicitedbystress.
NoticetheshifttowardmoreoxidizedREinthecurvescorrespondingtostressfulconditions.
Thethickgrayarrowpointingtotheleftdenotespathologicalconditionsarising,e.
g.
,fromchronicdiseases,whereseverestresswillaffectbothenergetic(e.
g.
,m,ADPconsumption)andredox[e.
g.
,NAD(P)H,GSH,Trx]functionsthusincreasedmitochondrialROSemissionandhighercytoplasmicROSlevels.
ReprintedfromCortassaetal.
(2014).
BasedonthepremiseofmetaboliclinksextendingbeyondphysicalcontactbetweenmitochondriaandLDs,weproposeamodelofmetabolicchannelingforlipidutilizationbymitochon-dria.
Accordingtoourmodel,metabolicchannelingrepresentsawaymitochondriacanmanagelipidafuenceinanenergeticallyandredox-controlledfashion.
Qualitatively,thelipidutilizationchannelingmodelpostulatesthatafterTAGdegradation,lipidsaredirectlydeliveredforactivation,transportandβ-oxidationfromtheLDtothemitochondrionatthecontactsite(Figure1).
Themodelalsoproposesthatβ-oxidationmayalsohappenmetabolicallychanneledthroughtheenzymaticcomponentsofthelipiddegradationpathwayorganizedasamultienzymecom-plex(Eaton,2002).
Fromastructuralstandpoint,themodelisbasedondirectandclosecontactbetweenLDsandmitochondriainvolvingtheirrecruitmentandsurroundingoftheLD.
Themodelalsopostulatesmembranefusion-mediatedreorganizationofintra-mitochondrialmembraneandmolecularcomponents(WaltherandFarese,2009)aswellaslipidssegregationwithinthedroplet(FujimotoandParton,2011).
Biochemically,thepathwayoflong-chainFAOtoAcCoAisoneofthelongestunbranchedpathwaysinmetabolism,contain-ing27intermediatesbetweenpalmitoyl-CoAandAcCoA(Eaton,2002).
Thattheenzymesofβ-oxidationmaybeorganizedintoamultienzymecomplexwassuggestedlongago.
Inthesebiomolec-ularassemblies,sequentialcatalyticreactionsproceedviatransferoftheintermediatesbetweenindividualcomponentenzymes,precludingtheirdiffusionintothebulkaqueousmedium,thus"metabolicallychanneled"(Welch,1977;Sumegietal.
,1991).
Anearlierproposalofmetabolicchannelinginβ-oxidationwasbasedonthedetectionoflowconcentrationsofintermedi-ates(Garlandetal.
,1965)andtheobservationthatβ-oxidationintermediatesthataccumulatebehavedmorelikeproductsthanintermediates(Stewartetal.
,1973;StanleyandTubbs,1974,1975;Eatonetal.
,1994,1996a,b,1999).
Thisledtothe"leakyhosepipe"modelforthecontrolofβ-oxidationux(Stewartetal.
,1973;StanleyandTubbs,1974,1975)inwhichchannelingofasmall,quicklyturning-overpoolofintermediateswasimplied(seeEaton,2002forareview).
Someaspectsofthestructuralbasisforachannelingmecha-nisminβ-oxidationhavebeendescribed(Ishikawaetal.
,2004).
EvidenceinsupportofamultifunctionalFAOcomplexwithinmitochondria,physicallyassociatedwithrespiratorychainsuper-complexesthatfavormetabolicchanneling,hasbeenrecentlyreported(Wangetal.
,2010).
Functionally,thedirectdeliveryoflipidsatcontactsites,andtheirchanneledprocessingwillavoidelevationoftheirconcentration,thusrulingoutthepotentialinhibitoryaswellasuncouplingactionofFAs(WojtczakandSchonfeld,1993).
Thelatterwillensureareliableandefcientenergysupply.
CONCLUDINGREMARKSMitochondria,cellsandorganshavedevelopedmechanismsthatallowmanagingheavyinuxofFAswithinfunctionallyreliablelimits.
TheLDasadynamicstorageofFAscanalsobeseenasaprotectivemechanismemployedbycellstoavoidexcessiveintracellularconcentrationofFAsthushinderingtheirpoten-tialdeleteriouseffectsonmitochondrialfunction.
Thetightandreciprocalregulationoflipidstorageandutilizationisevi-dencedbygeneticmanipulationofperilipinsindicatingthattheirreducedexpressionleadstoincreasedlipidoxidationandreducedaccumulationofintracellularfatandadiposemass.
Ontheotherhand,however,excessivelipolysisanddefectivelipidstoragepro-motesinsulinresistancethroughmitochondrialFAoverloadandROSoverow.
PreservationoftheintracellularREiscrucialforvitalfunc-tions.
Mitochondriaplayadecisiveroleastheorganellethatspecicallyhandlesthehighestamountsofoxygenprocessedbytheorganismthuspronenotonlytobethesourcebutalsothetargetofoxidativestress.
Mitochondrialfunctionneedstosus-tainenergysupplyreliablywhilereleasingROSlevelscompatiblewithsignaling.
However,lipidscanderailbothofthesecriticalfunctions.
Consequently,thehypotheticallipidutilizationchan-nelingmodelweareproposinghereinsatisesthefundamentalswww.
frontiersin.
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Mitochondrialfunctionandlipidexcessofcellularandmitochondrialenergeticsandredox.
Inprinciple,diversionofexcesslipidstoLDscanbeaneffectivecytoplasmicmechanismfor"sequestering"FAstherebyhelpingtokeeplowconcentrationoflipotoxicintermediatesresultingfromlipidoxi-dation.
Functionally,directdeliveryandchanneledprocessingoflipidsinmitochondriacouldrepresentareliableandefcientwaytoensureenergysupplyandredoxcontrol.
Suchamechanismwouldavoidexceedingthelipidstoragecapacitythusbecomingcrucialforskeletalmuscleorheartsubjectedtohighworkload,andtherefore,heavyinuxofFAs.
ACKNOWLEDGMENTSThisworkwassupportedbyNationalInstitutesofHealthgrantsR01-HL091923(MiguelA.
Aon)andR21HL106054(SoniaC.
Cortassa).
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1100747ConictofInterestStatement:Theauthorsdeclarethattheresearchwascon-ductedintheabsenceofanycommercialornancialrelationshipsthatcouldbeconstruedasapotentialconictofinterest.
Received:07April2014;accepted:10July2014;publishedonline:31July2014.
Citation:AonMA,BhattNandCortassaSC(2014)Mitochondrialandcellularmechanismsformanaginglipidexcess.
Front.
Physiol.
5:282.
doi:10.
3389/fphys.
2014.
00282ThisarticlewassubmittedtoMitochondrialResearch,asectionofthejournalFrontiersinPhysiology.
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