Table Of ContentHandbook of Neurochemistry and Molecular Neurobiology
BrainEnergetics.IntegrationofMolecularandCellularProcesses
Abel Lajtha (Ed.)
Handbook of
Neurochemistry and
Molecular Neurobiology
Brain Energetics. Integration of
Molecular and Cellular Processes
Volume Editors: Gary E. Gibson and Gerald A. Dienel
With198 Figures and51Tables
Editor
AbelLajtha
Director
CenterforNeurochemistry
NathanS.KlineInstituteforPsychiatricResearch
140OldOrangeburgRoad
Orangeburg
NewYork,10962
USA
VolumeEditors
GaryE.Gibson,Ph.D. GeraldA.Dienel,Ph.D.
ProfessorofNeuroscience Professor
DepartmentofNeurologyandNeuroscience Dept.NeurologyandPhysiology&Biophysics
WeillMedicalCollegeofCornellUniversity UniversityArkansasforMedicalSciences
BurkeMedicalResearchInstitute ShoreyBldg.Room715,MailSlot830
785MamaroneckAvenue 4301W.MarkhamSt.
WhitePlains,NY10605 LittleRock,AR72205
USA USA
[email protected] [email protected]
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Table of Contents
Preface .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. .. v
Contributors.. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. . xi
1 GlucoseMetabolisminBrain
1.1 Bioenergetics .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. .. 3
D.G.Nicholls
1.2 Glucose,OxidativeEnergyMetabolism,andNeuralFunctioninBrain
Slices—GlycolysisPlaysaKeyRoleinNeuralActivity. .. .. . .. .. .. . .. .. . 17
Y.Okada.P.Lipton
1.3 PentosePhosphatePathwayandNADPHMetabolism .. .. . .. .. .. . .. .. . 41
R.Dringen.H.H.Hoepken.T.Minich.C.Ruedig
1.4 TheCerebralTricarboxylicAcidCycles . .. .. .. . .. .. .. .. . .. .. .. . .. .. . 63
T.B.Rodrigues.S.Cerda´n
1.5 ElectronTransport.Structure,Redox‐CoupledProtonmotiveActivity,
andPathologicalDisordersofRespiratoryChainComplexes .. .. .. . .. .. . 93
S.Papa.V.Petruzzella.S.Scacco
1.6 TheMitochondrialF F ATPSynthase. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 119
1 o
A.Gaballo.S.Papa
2 AlternativeSubstrates
2.1 TheSupportofEnergyMetabolismintheCentralNervousSystem
withSubstratesOtherthanGlucose .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 137
E.L.Roberts,Jr
3 MetabolicSpecializationofBrainCellTypesandCompartmentationofFunction
3.1 Anaplerosis . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 183
B.Hassel
#Springer-VerlagBerlinHeidelberg2007
viii TableofContents
3.2 Glial–NeuronalShuttleSystems . .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 197
C.Zwingmann.D.Leibfritz
4 MolecularandCellularArchitectureLinkEnergyDemandwith
MetaboliteFluxes
4.1 CytoplasmicGlycolyticEnzymes.SynapticVesicle‐Associated
GlycolyticATP‐GeneratingEnzymes:CouplingtoNeurotransmitter
Accumulation .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 241
T.Ueda.A.Ikemoto
4.2 MitochondrialArchitectureandHeterogeneity. . .. .. .. .. . .. .. .. . .. .. 261
G.A.Perkins.M.H.Ellisman
4.3 CouplingofNeuronalFunctiontoOxygenandGlucoseMetabolism
ThroughChangesinNeurotransmitterDynamicsasRevealedwith
Aging,Hypoglycemia,andHypoxia .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 297
J.A.Joseph.G.E.Gibson
4.4 CouplingofBrainFunctionandMetabolism:EndogenousFlavoprotein
FluorescenceImagingofNeuralActivitiesbyLocalChangesin
EnergyMetabolism . . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 321
K.Shibuki.R.Hishida.H.Kitaura.K.Takahashi.M.Tohmi
4.5 CouplingofBrainFunctiontoMetabolism:EvaluationofEnergy
Requirements.. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 343
A.Gjedde
4.6 EnergyConsumptionbyPhospholipidMetabolisminMammalianBrain .. 401
A.D.Purdon.S.I.Rapoport
4.7 IonTransportandEnergyMetabolism . .. .. .. . .. .. .. .. . .. .. .. . .. .. 429
O.Vergun.K.E.Dineley.I.J.Reynolds
5 RegulationofMetabolicFluxesandMetabolicShuttlingbyNeuralEnvironment
5.1 Acid–BaseTransportandpHRegulation .. .. .. . .. .. .. .. . .. .. .. . .. .. 469
J.W.Deitmer
5.2 NitricOxideinRegulationofMitochondrialFunction,Respiration,and
Glycolysis .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 487
J.P.Bolan˜os.A.Almeida
5.3 MitochondrialProductionofOxidantsandTheirRoleintheRegulationof
CellularProcesses .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 519
P.S.Brookes
TableofContents ix
5.4 UncouplingProteins . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 549
J.S.Kim‐Han.S.S.Ali.L.L.Dugan
5.5 ActionsofToxinsonCerebralMetabolismattheCellularLevel.. .. . .. .. 569
U.Sonnewald.T.Syversen.A.Schousboe.H.Waagepetersen.M.Aschner
6 InteractionofMitochondriawithCytosolandOtherOrganelles
6.1 Mitochondrial/CytosolicInteractionsviaMetaboliteShuttlesand
Transporters. .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 589
K.F.LaNoue.V.Carson.D.A.Berkich.S.M.Hutson
6.2 Mitochondrial‐EndoplasmicReticulumInteractions .. .. .. . .. .. .. . .. .. 617
G.Szabadkai.R.Rizzuto
6.3 Mitochondria-NucleusEnergeticCommunication:Rolefor
PhosphotransferNetworksinProcessingCellularInformation .. .. . .. .. 641
P.P.Dzeja.A.Terzic
6.4 MitochondrialPermeabilityTransitionintheCNS—Composition,
Regulation,andPathophysiologicalRelevance. . .. .. .. .. . .. .. .. . .. .. 667
T.Wieloch.G.Mattiasson.M.J.Hansson.E.Elme´r
6.5 MitochondrialMechanismsofOxidativeStressandApoptosis .. .. . .. .. 703
L.Soane.N.Solenski.G.Fiskum
7 GenesofMetabolism:Generating,Sustaining,andModifyingthe
MachineryofEnergyMetabolism.RegulationofGeneExpressionfor
MetabolicEnzymes
7.1 Proteomics . . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 737
M.H.Maurer.W.Kuschinsky
7.2 GeneticsandGeneExpressionofGlycolysis . .. . .. .. .. .. . .. .. .. . .. .. 771
J.C.LaManna.P.Pichiule.J.C.Chavez
7.3 TranscriptionalIntegrationofMitochondrialBiogenesis .. . .. .. .. . .. .. 789
R.C.Scarpulla
8 MetabolicControlAnalysis:ModelingLocalPathwayFluxes,ControlPoints,
SystemInteractions,NetworkInteractions
8.1 MechanismsandModelingofEnergyTransferBetweenIntracellular
Compartments . .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 815
V.A.Saks.M.Vendelin.M.K.Aliev.T.Kekelidze.J.Engelbrecht
x TableofContents
8.2 ModelingofRegulationofGlycolysisandOverallEnergyMetabolism
UnderaSystemsBiologyApproach .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 861
M.Cascante.L.G.Boros.J.Boren
8.3 ModelingofElectronTransport:ImplicationstoMitochondrialDiseases.. 877
J‐P.Mazat.M.Beurton‐Aimar.B.Faustin.T.Letellier.M.Malgat.
C.Nazaret.R.Rossignol
8.4 Metabolomics:ConceptsandPotentialNeuroscienceApplications . . .. .. 889
B.S.Kristal.R.Kaddurah‐Daouk.M.F.Beal.W.R.Matson
Index . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 913
Preface
Thebraindependsuponacontinuoussupplyofglucoseandoxygenfornormalfunction,andreductionsin
brainmetabolismeithercauseorareassociatedwithmultipleneurodegenerativediseasesandstroke.Thus,
itisnotsurprisingthatenergymetabolismwasacentralaspectoftheearlydevelopmentofneurochemistry.
Classictextsofneurochemistry,includingChemistryoftheBrain,byI.H.Page(1937),Neurochemistry:The
ChemistryofBrainandNerve,editedbyK.A.C.Elliott,I.H.Page,andJ.H.Quastel(1962),Biochemistry
andtheCentralNervousSystem,byH.I.McIlwain(1971),BrainEnergyMetabolismbyB.Siesjo¨(1978),and
BasicNeurochemistry(R.W.Albersetal.,1stedition,1972;nowinits7thedition,2005),havefocusedon
energymetabolism.Sincethesetextswerewritten,newareasofneurochemistryhavebeenbornandhave
growntremendously,greatlyenhancingourunderstandingofbrainenergymetabolism.Duringthepast50
years, our understanding of the metabolic pathways in brain, their components, regulation, cellular
specialization, and cell–cell interactions has greatly expanded. As a consequence of these considerable
achievements,brainenergymetabolismissometimesviewedasamaturefieldinwhichthefundamental
problemshavebeenidentifiedandsolved.However,theseaccomplishmentshaveledtonewandevenmore
interestingquestions.
Seamless integration of energy metabolism, neurotransmission, and signaling pathways with cellular
structure and function is an implicit goal of neuroscience. Nevertheless, the interrelationships between
function and metabolism are often ignored due to increasing specialization within subdisciplines of
neuroscience. Thus, it is important to note that most assays of brain function are indirect, relying on
measurements of changes in levels or fluxes of endogenous energy metabolites or exogenous tracers
metabolized via energy-producing pathways. These processes provide signals that can be captured by
different methodologies, including optical techniques with infrared and fluorescence signals, magnetic
resonancespectroscopyorimaging,positronemissiontomography,aswellasbiochemicalassays.Multi-
disciplinaryapproachesarebecomingincreasinglynecessarytoprobedeeperintotherealmoffunctional
andmetabolicspecializationofbraincells.Tounderstandthebasisofthesefunctionalmetabolicsignals
and interpret their changes in terms of cellular and systems activities, particularly in disease states, it is
essentialforneuroscientiststoassimilateanunderstandingofthecomplexityandheterogeneityofenergy
metabolisminbrain.
Toprovideacomprehensiveresourceforstudiesofbrainfunctionandmetabolism,thisvolumefocuses
on aspects of energy metabolism that are unique to the brain. The goal of each chapter is to provide a
fundamental overview of each area, to define the state-of-the-art in that area as it relates to brain, and,
whereappropriate,describemodelsthatportraypoorlyunderstoodandapparentlycontradictorydatasets
withthegoalofhelpingfocusattentiontoexperimentalresolutionofcontroversialissues.Thecontentsof
thechaptersrangefromclassicalsubjectsthatwerecoveredintheearlytextstoareasandtechniquesthat
havenotyetbeenappliedtothebrain.Ourunderstandingofeventhetraditionalareasofmetabolism,such
asglycolysis,theKrebscycle,andelectrontransportchainischangingrapidly,andthesenewareasandideas
aredrivenbytheinnovativeandpowerfultechniquesofimaging,molecularbiology,generegulation,and
mathematicalanalysisandmodeling.
Weareparticularlygratefultoourexpertauthorsfortheiroutstandingcontributionstothiscompre-
hensivevolume.Eachchapterwasexhaustivelyreviewedandthenrevised,requiringanimmenseamountof
effort.Theexceptionalqualityofthechaptersreflectstheauthors’commitmenttoexcellencetoprovidea
resource for young and senior neuroscientists in all disciplines, and the complementary nature of their
chaptersmakethewholegreaterthanthesumoftheparts.
vi Preface
WethankDr.AbelLajtha,Editor-In-ChiefoftheHandbookofNeurochemistryandMolecularNeurobi-
ology,andSpringerforallowingustheopportunitytoeditthisvolumeonbrainenergymetabolism.Their
visionistopublishthethirdeditionoftheHandbookasabookversionforeasydeskreferenceplusaWeb
versionthatcanbeupdatedannuallyandeasilyaccessedbyanyoneintheworld.Weareexcitedaboutthis
uniqueopportunitytotakeadvantageofagreatfeatureoftwenty-firstcenturycommunicationbywayof
theWeb.Weanticipatethatthisvolumeonbrainenergymetabolismwillevolveinthefutureasauthors
bring new information to their chapters and as new chapters are added to describe emerging fields of
research.Bythismechanism,ourunderstandingofbrainenergeticsfromthelevelofgenestometabolitesto
cellswillbeintegratedintermsofmolecularandcellularprocessesthatsupportfunctionalsystems.
GaryE.GibsonandGeraldA.Dienel
Contributors
S.S.Ali L.G.Boros
DepartmentofMedicine,UniversityofCalifornia, UCLASchoolofMedicine,DivisionofPediatric
SanDiego,CA92093,USA Endocrinology,LosAngelesBiomedicalResearch
InstituteattheHarbor-UCLAMedicalCenter,
M.K.Aliev 1124WestCarsonStreet,RB1,Torrance,
CardiologyResearchCenter,InstituteofExperimental CA90502‐2910andSIDMAP,LLC,LosAngeles,
Cardiology,LaboratoryofCardiacPathology,121552 CA90064,USA
Moscow,Russia
P.S.Brookes
A.Almeida DepartmentofAnesthesiology,Box604,Universityof
UniversidaddeSalamanca,EdificioDepartamental, RochesterMedicalCenter,601ElmwoodAvenue,
CampusMigueldeUnamuno,37007Salamanca, Rochester,NY14642,USA
andHospitalUniversitariodeSalamanca,PaseodeSan [email protected]
Vicente58‐182,37007Salamanca,Spain
V.Carson
M.Aschner
PennsylvaniaStateCollegeofMedicine,Hershey,
DepartmentofPediatrics,B‐3307MedicalCenterNorth,
PA17033,USA
VanderbiltUniversityMedicalCenter,116221stAvenue,
Nashville,TN37232‐2495,USA
M.Cascante
[email protected]
DepartmentofBiochemistryandMolecularBiology,
UniversityofBarcelona,C/Mart´ıiFranque´s1,08028
M.F.Beal
Barcelona,Spain
DepartmentofNeuroscience,WeillMedicalCollegeof
[email protected]
CornellUniversity,525East68St.,NY,NY10021,USA
S.Cerda´n
D.A.Berkich
LaboratoryforImagingandSpectroscopybyMagnetic
PennsylvaniaStateCollegeofMedicine,Hershey,
Resonance(LISMAR),InstituteofBiomedicalResearch
PA17033,USA
‘‘AlbertoSols’’CSIC/UAM,c/ArturoDuperier4,E‐28029
Madrid,Spain
M.Beurton-Aimar
[email protected]
InsermU688,Universite´Bordeaux2,Bordeaux,France
J.P.Bolan˜os J.C.Chavez
UniversidaddeSalamanca,EdificioDepartamental, Burke/CornellMedicalResearchInstitute,785
CampusMigueldeUnamuno,37007Salamanca,Spain MamaroneckAve,WhitePlains,NY10605,USA
[email protected]
J.W.Deitmer
J.Boren Abteilungfu¨rAllgemeineZoologie,FBBiologie,
DepartmentofBiochemistryandMolecularBiology, TUKaiserslautern,P.B.3049,D‐67653Kaiserslautern,
UniversityofBarcelona,C/Mart´ıiFranque´s1, Germany
08028Barcelona,Spain [email protected]
#Springer-VerlagBerlinHeidelberg2007
