Mitochondrial DNA - Methods and Protocols

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1、MethodsinMolecularBiologyMethodsinMolecularBiologyTMVOLUME197MitochondrialMitochondrialDNADNAMethodsandProtocolsMethodsandProtocolsEditedbyEditedbyWWilliamC.CopelandilliamC.CopelandHUMANAPRESSAnimalModelsforMitochondrialDisease1IMETHODSFORTHEANALYSISOFMTDNAAnimalModelsforMitochondrialDi

2、sease31AnimalModelsforMitochondrialDiseaseDouglasC.Wallace1.IntroductionAlthoughavarietyofdegenerativediseasesarenowknowntobecausedbytwomutationsinmitochondrialgenes,thepathophysiologyofthesediseasesremainspoorlyunderstood.Asaconsequence,relativelylittleprogresshasbeenmadeindevelopingne

3、wtherapiesformitochondrialdiseases.Whathasbeenneededareanimalmodelsforthesediseasesthatareamenabletodetailedbiochemical,physiological,andmolecularanalysis,andonwhichpromisingtherapiescanbetested.Inthepast5yr,thisdeficiencyhasbeguntobeaddressedbytheconstructionofanumberofmousemodelsofmito

4、chon-drialdisease.Thesehavealreadyrevolutionizedourunderstandingofthepathophysiologyofmitochondrialdiseaseanddemonstratedtheefficacyofsomenewantioxidantdrugs.1.1.MitochondrialBiologyandGeneticsThemitochondriageneratemuchofthecellularenergythroughtheprocessofoxidativephosphorylation(OXPHO

5、S).Asabyproduct,theyproducemostoftheendogenoustoxicreactiveoxygenspecies(ROS).Themitochondrialarealsothecentralregulatorofapoptosis(programmedcelldeath),aprocessinitiatedbytheactivationofthemitochondrialpermeabilitytransitionpore(mtPTP).Theseinterrelatedmitochondrialsystemsareassembledf

6、romroughly1000genesdistributedbetweenthetwoverydifferentgeneticsystemsofthemammaliancell:thenucleargenomeandthemitochondrialgenome.Hence,thecomplexitiesofmitochondrialdiseasereflecttheintricaciesofboththephysiologyandthegeneticsofthemitochondrion.From:MethodsinMolecularBiology,vol.197:Mi

7、tochondrialDNA:MethodsandProtocolsEditedby:W.C.Copeland©HumanaPressInc.,Totowa,NJ34Wallace1.1.1.MitochondrialPhysiologyTounderstandthepathophysiologyofmitochondrialdiseases,itisnecessarytounderstandthephysiologyofOXPHOS.Themitochondriaoxidizehydrogenderivedfromcarbohydratesandf