Novel Mitochondrial Substrates of Omi Indicate a New Regulatory Role in Neurodegenerative Disorders 英文参考文献.docVIP
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Novel Mitochondrial Substrates of Omi Indicate a New Regulatory Role in Neurodegenerative Disorders 英文参考文献
NovelMitochondrialSubstratesofOmiIndicateaNew
RegulatoryRoleinNeurodegenerativeDisorders
FelicityJohnson*,MichaelG.Kaplitt
DepartmentofNeurologicalSurgery,CornellUniversity,WeillMedicalCollege,NewYork,NewYork,UnitedStatesofAmerica
Abstract
The mitochondrial protease OMI (also known as HtrA2) has been implicated in Parkinson’s Disease (PD) and deletion or
proteasedomainpointmutationshaveshownprofoundneuropathologiesinmice.AbeneficialrolebyOMI,inpreservingcell
viability, is assumed to occur via the avoidance of dysfunctional protein turnover. However relatively few substrates for
mitochondrial Omi are known. Here we report our identification of three novel mitochondrial substrates that impact
metabolismandATPproduction.Usingadualproteomicapproachwehaveidentifiedthreeinteractorsbaseduponabilityto
bindtoOMI,and/ortopersistintheproteomeafterOMIactivityhasbeenselectivelyinhibited.Onecandidate,thechaperone
HSPA8,wascommontoeachindependentstudy.Twoothers(PDHBsubunitandIDH3Asubunit)didnotappeartobindto
OMI, however persisted in the mito-proteome when OMI was inhibited. Pyruvate dehydrogenase (PDH) and isocitrate
dehydrogenase(IDH)aretwokeyKreb’scycleenzymesthatcatalyseoxidativedecarboxylationcontrolpointsinmitochondrial
respiration. We verified both PDHB and IDH3A co-immunoprecipitate with HSPA8 and after elution, were degraded by
recombinantHtrA2invitro.Additionallyourgeneexpressionstudies,usingrotenone(aninhibitorofComplexI)showedOmi
expressionwassilencedwhenpdhbandidh3awereincreasedwhenasub-lethaldosewasapplied.Howeverhigherdose
treatmentcausedincreasedOmiexpressionanddecreasedlevelsofpdhbandidh3atranscripts.Thisimplicatesmitochondrial
OMIinanovelmechanismrelatingtometabolism.
Citation:JohnsonF,KaplittMG(2009)NovelMitochondrialSubstratesofOmiIndicateaNewRegulatoryRoleinNeurodegenerativeDisorders.PLoSONE4(9):
e7100.doi:10.1371/journal.pone.0007100
Editor:MarkR.Cookson,NationalInstitutesofHealth,UnitedStatesofAmerica
ReceivedMarch9,2009;AcceptedAugust19,2009;PublishedSeptem
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