Screening for Active Small Molecules in Mitochondrial Complex I Deficient Patients Fibroblasts, Reveals AICAR as the Most Beneficial Compound 英文参考文献.docVIP

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Screening for Active Small Molecules in Mitochondrial Complex I Deficient Patients Fibroblasts, Reveals AICAR as the Most Beneficial Compound 英文参考文献.doc

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Screening for Active Small Molecules in Mitochondrial Complex I Deficient Patients Fibroblasts, Reveals AICAR as the Most Beneficial Compound 英文参考文献

ScreeningforActiveSmallMoleculesinMitochondrial ComplexIDeficientPatient’sFibroblasts,RevealsAICAR astheMostBeneficialCompound AnnaGolubitzky1.,PhyllisDan1.,SarahWeissman1,GabrielaLink1,JakobD.Wikstrom2,AnnSaada1* 1Monique and Jacques Roboh Department of Genetic Research, Department of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem,Israel,2DepartmentofEndocrinologyandMetabolism,Hadassah,HebrewUniversityMedicalCenter,Jerusalem,Israel Abstract CongenitaldeficiencyofthemitochondrialrespiratorychaincomplexI(CI)isacommondefectofoxidativephosphorylation (OXPHOS). Despite major advances in the biochemical and molecular diagnostics and the deciphering of CI structure, functionassemblyandpathomechanism,thereiscurrentlynosatisfactorycureforpatientswithmitochondrialcomplexI defects.Smallmoleculesprovideonefeasibletherapeuticoption,howevertheirusehasnotbeensystematicallyevaluated usingastandardizedexperimentalsystem.Inordertoevaluatepotentiallytherapeuticcompounds,wesetuparelatively simplesystemmeasuringdifferentparametersusingonlyasmallamountofpatient’sfibroblasts,inglucosefreemedium, wheregrowthishighlyOXPOSdependent.TendifferentcompoundswerescreenedusingfibroblastsderivedfromsevenCI patients, harboring different mutations. 5-Aminoimidazole-4-carboxamide ribotide (AICAR) was found to be the most beneficial compound improving growth and ATP content while decreasing ROS production. AICAR also increased mitochondrial biogenesis without altering mitochondrial membrane potential (Dy). Fluorescence microscopy data supported increased mitochondrial biogenesis and activation of the AMP activated protein kinase (AMPK). Other compounds such as; bezafibrate and oltipraz were rated as favorable while polyphenolic phytochemicals (resverastrol, grapeseedextract,genisteinandepigallocatechingallate)werefoundnotsignificantordetrimental.Althoughtheresults have to be verified by more thorough investigation of additional OXPHOS parameters, preliminary r