2024
Sulfide quinone oxidoreductase contributes to voltage sensing of the mitochondrial permeability transition pore
Griffiths K, Wang A, Jonas E, Levy R. Sulfide quinone oxidoreductase contributes to voltage sensing of the mitochondrial permeability transition pore. The FASEB Journal 2024, 38: e23494. PMID: 38376922, PMCID: PMC11082757, DOI: 10.1096/fj.202301280r.Peer-Reviewed Original ResearchConceptsMitochondrial permeability transition poreSulfide quinone oxidoreductasePermeability transition poreTransition poreFragile X syndromeQuinone oxidoreductaseMouse heart mitochondriaHeart mitochondriaGenetic silencingAlzheimer's diseaseCardiac mitochondriaPharmacological inhibitionMitochondriaOpen probabilityOxidoreductaseX syndromeTherapeutic targetIncreased expressionModel systemLack of translationVoltage-gated channelsIsolated-perfused heartsPathological openingMyocardial ischemiaClinical therapy
2023
Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus
MacColl Garfinkel A, Mnatsakanyan N, Patel J, Wills A, Shteyman A, Smith P, Alavian K, Jonas E, Khokha M. Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus. Developmental Cell 2023, 58: 2597-2613.e4. PMID: 37673063, PMCID: PMC10840693, DOI: 10.1016/j.devcel.2023.08.015.Peer-Reviewed Original ResearchConceptsSpemann-Mangold organizerATP productionMitochondrial respirationC subunit ringHIF-1αMitochondrial oxidative metabolismEmbryonic patterningCell fateATP synthaseC subunitVentral mesodermHIF-1α activationInstructive roleHypoxia-inducible factor-1αΒ-cateninGeneral mechanismXenopusFactor-1αRespirationMembrane leakOxidative metabolismMetabolismMesodermActivationOxygen consumption
2022
Alpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL
Park HA, Crowe-White KM, Ciesla L, Scott M, Bannerman S, Davis AU, Adhikari B, Burnett G, Broman K, Ferdous KA, Lackey KH, Licznerski P, Jonas EA. Alpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL. Nutrition Research 2022, 101: 31-42. PMID: 35366596, PMCID: PMC9081260, DOI: 10.1016/j.nutres.2022.02.007.Peer-Reviewed Original ResearchConceptsPrimary hippocampal neuronsControl neuronsHippocampal neuronsAlpha-tocotrienolBcl-xLVitamin E familyCerebral ischemiaNeuronal viabilityMature neuronsB cellsNeurite complexityNeuronal functionMitochondrial energy productionBrain developmentCentral mechanismsNeuronsBeneficial effectsOxidative stressBcl-xL upregulationProtein levelsNeurite branchingTreatmentE familyATP levelsNeurite outgrowth
2021
Presynaptic Kv3 channels are required for fast and slow endocytosis of synaptic vesicles
Wu XS, Subramanian S, Zhang Y, Shi B, Xia J, Li T, Guo X, El-Hassar L, Szigeti-Buck K, Henao-Mejia J, Flavell RA, Horvath TL, Jonas EA, Kaczmarek LK, Wu LG. Presynaptic Kv3 channels are required for fast and slow endocytosis of synaptic vesicles. Neuron 2021, 109: 938-946.e5. PMID: 33508244, PMCID: PMC7979485, DOI: 10.1016/j.neuron.2021.01.006.Peer-Reviewed Original ResearchConceptsSlow endocytosisVesicle mobilizationF-actin cytoskeletonChannel mutationsPotassium channelsKv3.3 proteinsInhibits endocytosisRapid endocytosisNovel functionF-actinEndocytosisCrucial functionSynaptic vesiclesFamily channelsSynaptic transmissionDiscovery decadesMembrane potentialNeurotransmitter releaseDiverse neurological disordersIon conductanceMutationsReleasable poolMouse nerve terminalsPotassium channel mutationsPathological effects
2020
ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome
Licznerski P, Park HA, Rolyan H, Chen R, Mnatsakanyan N, Miranda P, Graham M, Wu J, Cruz-Reyes N, Mehta N, Sohail S, Salcedo J, Song E, Effman C, Effman S, Brandao L, Xu GN, Braker A, Gribkoff VK, Levy RJ, Jonas EA. ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome. Cell 2020, 182: 1170-1185.e9. PMID: 32795412, PMCID: PMC7484101, DOI: 10.1016/j.cell.2020.07.008.Peer-Reviewed Original ResearchConceptsFragile X syndromeC subunitAberrant synaptic developmentHuman fragile X syndromeATP synthase enzymeMental retardation proteinX syndromeATP production efficiencyMRNA translation rateAberrant cellular metabolismATP synthaseMRNA translationTranslation rateCellular metabolismSynaptic growthSynthase enzymeMouse neuronsSynapse maturationSynaptic developmentPharmacological inhibitionLeak channelsSynaptic maturationMembrane leakMaturationMetabolismThe new role of F1Fo ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection
Mnatsakanyan N, Jonas EA. The new role of F1Fo ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection. Experimental Neurology 2020, 332: 113400. PMID: 32653453, PMCID: PMC7877222, DOI: 10.1016/j.expneurol.2020.113400.Peer-Reviewed Original ResearchConceptsMitochondrial inner membraneATP synthaseInner membraneOxidative phosphorylationF1Fo-ATP synthaseUnique rotational mechanismMitochondrial inner membrane potentialEfficient cellular metabolismInner membrane potentialMitochondrial permeability transition porePermeability transition poreUnique regulatorAbundant proteinsNew roleCellular metabolismCell lifeProton translocationATP synthesisTransition poreCell survivalElectrochemical gradientCertain pathophysiological conditionsSynthaseATPMembrane potentialATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration
Mnatsakanyan N, Jonas EA. ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration. Journal Of Molecular And Cellular Cardiology 2020, 144: 109-118. PMID: 32461058, PMCID: PMC7877492, DOI: 10.1016/j.yjmcc.2020.05.013.Peer-Reviewed Original ResearchConceptsMitochondrial permeability transition poreC subunit ringMitochondrial permeability transitionPermeability transitionRegulator of metabolismPermeability transition poreImportant metabolic regulatorMitochondrial megachannelBiology todayRegulatory mechanismsCentral playerTransition poreMetabolic regulatorMolecular compositionRecent findingsRegulatorDegenerative diseasesPathophysiological roleRecent advancesMegachannelRoleMetabolismMysterious phenomenonInefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome
Griffiths KK, Wang A, Wang L, Tracey M, Kleiner G, Quinzii CM, Sun L, Yang G, Perez‐Zoghbi J, Licznerski P, Yang M, Jonas EA, Levy RJ. Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome. The FASEB Journal 2020, 34: 7404-7426. PMID: 32307754, PMCID: PMC7692004, DOI: 10.1096/fj.202000283rr.Peer-Reviewed Original ResearchConceptsFragile X syndromeProton leakMental retardation protein (FMRP) expressionInefficient oxidative phosphorylationX syndromeCoenzyme Q deficiencyThermogenic respirationMitochondrial CoQTranscriptional silencingFMRP deficiencyFmr1 knockout miceQ deficiencyDysfunctional mitochondriaFMR1 geneFXS phenotypeOxidative phosphorylationMitochondrial respirationCommon genetic causeProtein synthesisFull mutationKey phenotypicPeak of synaptogenesisMitochondriaProtein expressionGenetic cause
2019
Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons
Park HA, Mnatsakanyan N, Broman K, Davis AU, May J, Licznerski P, Crowe-White KM, Lackey KH, Jonas EA. Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons. International Journal Of Molecular Sciences 2019, 21: 220. PMID: 31905614, PMCID: PMC6982044, DOI: 10.3390/ijms21010220.Peer-Reviewed Original ResearchConceptsPrimary hippocampal neuronsHippocampal neuronsReactive oxygen speciesMitochondrial dysfunctionBcl-xLMitochondrial membrane potentialMitochondrial functionProduction of ROSExcitotoxic conditionsGlutamate challengeNeuroprotective propertiesMembrane potentialNeuronal deathExcitotoxic stimulationBcl-xL levelsNeuronal survivalIntracellular ATP depletionMitochondrial reactive oxygen speciesB cellsImportant causeDysfunctionNeuronsROS productionATP depletionNeurite outgrowthA mitochondrial megachannel resides in monomeric F1FO ATP synthase
Mnatsakanyan N, Llaguno MC, Yang Y, Yan Y, Weber J, Sigworth FJ, Jonas EA. A mitochondrial megachannel resides in monomeric F1FO ATP synthase. Nature Communications 2019, 10: 5823. PMID: 31862883, PMCID: PMC6925261, DOI: 10.1038/s41467-019-13766-2.Peer-Reviewed Original ResearchConceptsATP synthase monomersMitochondrial permeability transition poreATP synthaseGiant unilamellar vesiclesMitochondrial megachannelOligomeric stateSmall unilamellar vesiclesF1Fo-ATP synthaseMitochondrial ATP synthaseMitochondrial inner membraneCryo-EM density mapsPermeability transition porePorcine heart mitochondriaUnilamellar vesiclesInner membraneMPTP activityTransition poreElectron cryomicroscopyChannel activityLipid compositionDimer formationHeart mitochondriaSynthaseChannel formationVesiclesParkinson’s disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth
Chen R, Park HA, Mnatsakanyan N, Niu Y, Licznerski P, Wu J, Miranda P, Graham M, Tang J, Boon AJW, Cossu G, Mandemakers W, Bonifati V, Smith PJS, Alavian KN, Jonas EA. Parkinson’s disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth. Cell Death & Disease 2019, 10: 469. PMID: 31197129, PMCID: PMC6565618, DOI: 10.1038/s41419-019-1679-x.Peer-Reviewed Original ResearchConceptsDJ-1C subunitATP synthaseParkinson's disease protein DJ-1Β-subunitProtein componentsATP synthase β subunitMitochondrial uncouplingDJ-1 bindsATP synthase efficiencyATP synthase F1Synthase β subunitATP production efficiencyProtein DJ-1Neuronal process extensionProtein levelsNeuronal process outgrowthDJ-1 knockoutWild-type counterpartsSubunit protein levelsDJ-1 mutationsSevere defectsCell metabolismKO neuronsKO culturesThe mitochondrial metabolic function of DJ‐1 is modulated by 14‐3‐3β
Weinert M, Millet A, Jonas EA, Alavian KN. The mitochondrial metabolic function of DJ‐1 is modulated by 14‐3‐3β. The FASEB Journal 2019, 33: 8925-8934. PMID: 31034784, PMCID: PMC6988861, DOI: 10.1096/fj.201802754r.Peer-Reviewed Original ResearchConceptsMitochondrial metabolic efficiencyMitochondrial metabolic functionDisease genesMetabolic efficiencyMetabolic functionsMajor signaling pathwaysNovel molecular mechanismHypoxia-dependent mannerParkinson's disease genesKey adaptive mechanismsMitochondrial plasticityChaperone activityCellular metabolic demandsMetabolic plasticityReactive oxygen speciesMolecular mechanismsOxidative phosphorylationPleiotropic functionsSignaling pathwaysDJ-1Cell survivalCancer cellsOxygen speciesAdaptive mechanismsPathophysiological conditions
2018
Nutritional Regulators of Bcl-xL in the Brain
Park HA, Broman K, Stumpf A, Kazyak S, Jonas EA. Nutritional Regulators of Bcl-xL in the Brain. Molecules 2018, 23: 3019. PMID: 30463183, PMCID: PMC6278276, DOI: 10.3390/molecules23113019.Peer-Reviewed Original ResearchConceptsBcl-xLNormal brain developmentNeuroprotective propertiesBcl-xL expressionB cellsBrain developmentBcl-2 proteinAnti-apoptotic Bcl-2 proteinPathological processesSafe strategyToxic stimulationHuman subjectsMitochondrial functionRegulatory effectsBrainNutritional regulatorsDiseaseNeuronsPathology
2017
Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases
Connolly NMC, Theurey P, Adam-Vizi V, Bazan NG, Bernardi P, Bolaños JP, Culmsee C, Dawson VL, Deshmukh M, Duchen MR, Düssmann H, Fiskum G, Galindo MF, Hardingham GE, Hardwick JM, Jekabsons MB, Jonas EA, Jordán J, Lipton SA, Manfredi G, Mattson MP, McLaughlin B, Methner A, Murphy AN, Murphy MP, Nicholls DG, Polster BM, Pozzan T, Rizzuto R, Satrústegui J, Slack RS, Swanson RA, Swerdlow RH, Will Y, Ying Z, Joselin A, Gioran A, Moreira Pinho C, Watters O, Salvucci M, Llorente-Folch I, Park DS, Bano D, Ankarcrona M, Pizzo P, Prehn JHM. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death & Differentiation 2017, 25: 542-572. PMID: 29229998, PMCID: PMC5864235, DOI: 10.1038/s41418-017-0020-4.Peer-Reviewed Original ResearchConceptsNeurodegenerative diseasesMitochondrial dysfunctionCellular modelSpectrum of chronicDeath of neuronsViable therapeutic targetPrimary neuron culturesMost neurodegenerative diseasesMitochondrial bioenergetic dysfunctionProgressive degenerationConsensus articleTherapeutic targetNeuron culturesDysfunctionSuch dysfunctionDiseaseHuntington's diseaseNeurodegenerative disease phenotypesBioenergetic dysfunctionDistinct molecular mechanismsCross-disease analysisDisease phenotypeMitochondrial functionCellular bioenergeticsMolecular mechanismsInhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity
Park HA, Licznerski P, Mnatsakanyan N, Niu Y, Sacchetti S, Wu J, Polster BM, Alavian KN, Jonas EA. Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity. Cell Death & Differentiation 2017, 24: 1963-1974. PMID: 28777375, PMCID: PMC5635221, DOI: 10.1038/cdd.2017.123.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBcl-X ProteinBiphenyl CompoundsCell DeathCyclosporineGlutamic AcidMembrane Potential, MitochondrialMitochondrial MembranesMitochondrial Proton-Translocating ATPasesModels, BiologicalMutant ProteinsNeuritesNeurotoxinsNitrophenolsPiperazinesProtein SubunitsRats, Sprague-DawleyRhodaminesSulfonamidesConceptsBcl-xLABT-737ΔN-BclMitochondrial membraneWEHI-539ATP synthase c-subunitMitochondrial inner membrane depolarizationPro-death actionInner membrane depolarizationMitochondrial inner membraneOuter mitochondrial membraneMitochondrial inner membrane potentialATP synthase activityActivation of BaxInner membrane potentialMitochondrial permeability transition poreMitochondrial membrane potentialMembrane potentialPermeability transition poreAnti-apoptotic activityC subunitInner membraneB-cell lymphoma extra-large proteinBax activationGlutamate toxicityNeuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis
Zille M, Karuppagounder SS, Chen Y, Gough PJ, Bertin J, Finger J, Milner TA, Jonas EA, Ratan RR. Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke 2017, 48: 1033-1043. PMID: 28250197, PMCID: PMC5613764, DOI: 10.1161/strokeaha.116.015609.Peer-Reviewed Original ResearchConceptsCell death mechanismsCaspase-dependent apoptosisDeath mechanismsMolecular markersChemical inhibitorsCell death pathwaysNecroptotic cell deathSecondary injuryNecroptotic signalingDeath pathwaysNecrotic phenotypeIntracerebral hemorrhageCell deathMRNA synthesisNecroptosisIntracerebral hemorrhage (ICH) resultsShare featuresFerroptosisHemin-induced toxicityFerroptosis inhibitorsAutophagyCultured neuronsApoptosisHemorrhage resultsNeuronal necrosis
2016
Editorial note
Peixoto PM, Pavlov E, Jonas E. Editorial note. Journal Of Bioenergetics And Biomembranes 2016, 49: 1-2. PMID: 27714488, DOI: 10.1007/s10863-016-9679-3.Peer-Reviewed Original ResearchThe Mitochondrial Permeability Transition Pore and ATP Synthase
Beutner G, Alavian K, Jonas EA, Porter GA. The Mitochondrial Permeability Transition Pore and ATP Synthase. Handbook Of Experimental Pharmacology 2016, 240: 21-46. PMID: 27590224, PMCID: PMC7439278, DOI: 10.1007/164_2016_5.BooksConceptsPermeability transition poreElectron transport chainATP synthaseGeneration of ATPMitochondrial permeability transition poreATP generationTransition poreCell deathC subunit ringMitochondrial ATP generationFo subunitsEmbryonic mouse heartPTP openingTransport chainOxidative phosphorylationEquivalents NADHMature cellsSynthasePhysiologic roleMouse heartsATPRecent studiesPhosphorylationSubunitsFADH2Physiological roles of the mitochondrial permeability transition pore
Mnatsakanyan N, Beutner G, Porter GA, Alavian KN, Jonas EA. Physiological roles of the mitochondrial permeability transition pore. Journal Of Bioenergetics And Biomembranes 2016, 49: 13-25. PMID: 26868013, PMCID: PMC4981558, DOI: 10.1007/s10863-016-9652-1.BooksConceptsMitochondrial permeability transition poreATP synthaseOxidative phosphorylationATP productionMulti-protein enzymeF1Fo-ATP synthaseMembrane potential maintenanceInner mitochondrial membraneSynaptic vesicle recyclingMembrane-inserted portionPermeability transition poreMitochondrial permeability transitionRegulatory complexC subunitCellular functionsVesicle recyclingMitochondrial membraneCardiac developmentRegulatory mechanismsMitochondrial productionTransition porePermeability transitionPhysiological roleCell deathEnzymatic portion
2015
Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress
Licznerski P, Duric V, Banasr M, Alavian KN, Ota KT, Kang HJ, Jonas EA, Ursano R, Krystal JH, Duman RS, . Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress. PLOS Biology 2015, 13: e1002282. PMID: 26506154, PMCID: PMC4623974, DOI: 10.1371/journal.pbio.1002282.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsBehavior, AnimalCohort StudiesDendritic SpinesDepressive Disorder, MajorEnzyme RepressionFemaleGene Transfer TechniquesHippocampusHumansImmediate-Early ProteinsMaleMiddle AgedNerve Tissue ProteinsNeuronsPrefrontal CortexProtein Serine-Threonine KinasesRats, Sprague-DawleySignal TransductionStress Disorders, Post-TraumaticSynaptic TransmissionTissue BanksConceptsMajor depressive disorderPost-traumatic stress disorderPrefrontal cortexAbnormal dendritic spine morphologyCorticolimbic brain regionsAnhedonic-like behaviorInhibition of SGK1Dendritic spine morphologyKinase 1 expressionAmygdala of individualsTraumatic stressPostmortem prefrontal cortexSynaptic dysfunctionDepressive disorderBehavioral deficitsRodent modelsPTSD subjectsFunctional alterationsBrain regionsSGK1 expressionSpine morphologyStress disorderFunction contributesBehavioral changesDisorders