2022
Mitochondrial ATP synthase c-subunit leak channel triggers cell death upon loss of its F1 subcomplex
Mnatsakanyan N, Park HA, Wu J, He X, Llaguno MC, Latta M, Miranda P, Murtishi B, Graham M, Weber J, Levy RJ, Pavlov EV, Jonas EA. Mitochondrial ATP synthase c-subunit leak channel triggers cell death upon loss of its F1 subcomplex. Cell Death & Differentiation 2022, 29: 1874-1887. PMID: 35322203, PMCID: PMC9433415, DOI: 10.1038/s41418-022-00972-7.Peer-Reviewed Original ResearchConceptsMitochondrial permeability transitionATP synthase c-subunitCell deathMitochondrial ATP synthaseChannel activityCellular energy productionLeak channelsVoltage-gated ion channelsF1 subcomplexATP synthaseC subunitInner membraneProkaryotic hostsCell stressPermeability transitionIon channelsGating mechanismOsmotic changesLarge conductanceC-ringChannels triggersNeuronal deathF1SubcomplexOsmotic gradient
2019
A 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 formationVesiclesATP Synthase C-Subunit-Deficient Mitochondria Have a Small Cyclosporine A-Sensitive Channel, but Lack the Permeability Transition Pore
Neginskaya MA, Solesio ME, Berezhnaya EV, Amodeo GF, Mnatsakanyan N, Jonas EA, Pavlov EV. ATP Synthase C-Subunit-Deficient Mitochondria Have a Small Cyclosporine A-Sensitive Channel, but Lack the Permeability Transition Pore. Cell Reports 2019, 26: 11-17.e2. PMID: 30605668, PMCID: PMC6521848, DOI: 10.1016/j.celrep.2018.12.033.Peer-Reviewed Original ResearchConceptsMitochondrial PT poreC subunitPermeability transitionMitochondrial inner membrane permeabilityPermeability transition poreInner membrane permeabilityATP synthasePT poreBongkrekic acidLarge conductance channelTransition poreMitochondrial functionCell deathParental cellsMitochondriaChannel activityMembrane permeabilityLow-conductance channelsConductance channelLow conductanceSensitive channelsSynthaseConductanceCellsDisruption
2017
Examination of Mitochondrial Ion Conductance by Patch Clamp in Intact Neurons and Mitochondrial Membrane Preparations
Jonas E, Mnatsakanyan N. Examination of Mitochondrial Ion Conductance by Patch Clamp in Intact Neurons and Mitochondrial Membrane Preparations. Neuromethods 2017, 123: 211-238. DOI: 10.1007/978-1-4939-6890-9_11.Peer-Reviewed Original ResearchMitochondrial calcium uniporterMitochondrial permeability transition poreInner membraneCell deathOuter membraneIon channelsBcl-2 family proteinsNumerous cellular processesMitochondrial ion channelsComplex of proteinsChannel activityTrafficking of metabolitesPro-death stimuliMitochondrial membrane preparationsPermeability transition poreIon channel activityMembrane compartmentalizationIon channel complexDeath channelATP synthaseCellular processesFamily proteinsCalcium uniporterMolecular participantsATP production
2014
Bcl-xL in neuroprotection and plasticity
Jonas EA, Porter GA, Alavian KN. Bcl-xL in neuroprotection and plasticity. Frontiers In Physiology 2014, 5: 355. PMID: 25278904, PMCID: PMC4166110, DOI: 10.3389/fphys.2014.00355.BooksMitochondrial outer membrane permeabilizationBcl-xLSynapse formationOuter membrane permeabilizationMaster regulator proteinBcl-2 family member Bcl-xLPro-death factorsPro-apoptotic factorsNeurodegenerative diseasesVesicular traffickingSpecialized proteinsRegulator proteinMembrane permeabilizationCell stressBioenergetic efficiencyHigh metabolic demandsNeurodegenerative stimuliProteinNormal neuronal activityChannel activityNeuronal functionGenetic mutationsSuch protective strategiesNeuroprotective strategiesNeuronal death
2013
Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticity
Jonas EA. Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticity. Biochimica Et Biophysica Acta 2013, 1842: 1168-1178. PMID: 24240091, PMCID: PMC4018426, DOI: 10.1016/j.bbadis.2013.11.007.Peer-Reviewed Original ResearchConceptsBcl-xLCaspase activationAnti-death proteinCell death stimuliMitochondrial membrane permeabilitySub-cellular membranesSynaptic vesicle recyclingNeuronal plasticityNormal neuronal plasticityInhibitor ABT-737Ion channel activityMitochondrial Bcl-xLMitochondrial positioningDeath stimuliMitochondrial releaseVesicle recyclingSynaptic growthMitochondrial functionNeurite retractionNeuronal activitySynaptic strengthSynaptic efficacyABT-737Channel activityLong-term decline
2012
N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death
Ofengeim D, Chen YB, Miyawaki T, Li H, Sacchetti S, Flannery RJ, Alavian KN, Pontarelli F, Roelofs BA, Hickman JA, Hardwick JM, Zukin RS, Jonas EA. N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death. Nature Neuroscience 2012, 15: 574-580. PMID: 22366758, PMCID: PMC3862259, DOI: 10.1038/nn.3054.Peer-Reviewed Original ResearchMouse Transient Global Ischemia Two-Vessel Occlusion Model.
Pontarelli F, Ofengeim D, Zukin RS, Jonas EA. Mouse Transient Global Ischemia Two-Vessel Occlusion Model. Bio-protocol 2012, 2 PMID: 27446974, PMCID: PMC4950949, DOI: 10.21769/bioprotoc.262.Peer-Reviewed Original ResearchMitochondrial channel activityTransient global ischemiaTwo-vessel occlusion modelBcl-2 family proteinsGlobal ischemiaOcclusion modelChannel activityCaspase-resistant formFamily proteinsFour-vessel occlusion modelCaspase activationHuman cardiac arrestNeocortical layers IIHippocampal CA1 neuronsHigh morbidity rateTransgenic animalsBcl-xLRegional strokeHilar neuronsAspiny neuronsFocal ischemiaMorbidity ratePyramidal neuronsCA1 neuronsCardiac arrest
2009
Mitochondrial Ion Channels in Ischemic Brain
Jonas E. Mitochondrial Ion Channels in Ischemic Brain. Contemporary Clinical Neuroscience 2009, 117-150. DOI: 10.1007/978-1-60327-579-8_7.Peer-Reviewed Original ResearchIon channel activityBcl-2 family proteinsCell deathMitochondrial intermembrane spaceCytochrome cMitochondrial ion channelsChannel activityEnergy-dependent eventsIntermembrane spaceIon channel componentsCellular processesFamily proteinsInner membraneOuter membraneOxidative phosphorylationCell lifeProapoptotic factorsProapoptotic moleculesMitochondriaIon channelsCytosolic levelsCurrent knowledgeNormal brain functionDependent eventsEnergy deprivation
2008
Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons
Miyawaki T, Mashiko T, Ofengeim D, Flannery RJ, Noh KM, Fujisawa S, Bonanni L, Bennett MV, Zukin RS, Jonas EA. Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2008, 105: 4892-4897. PMID: 18347331, PMCID: PMC2290755, DOI: 10.1073/pnas.0800628105.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBcl-Associated Death ProteinBcl-X ProteinBrain IschemiaCaspase InhibitorsChromonesHippocampusIon Channel GatingIschemic PreconditioningLarge-Conductance Calcium-Activated Potassium ChannelsMaleMitochondriaMorpholinesNeuronsPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein TransportProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleySignal TransductionConceptsMitochondrial outer membraneSmac/DIABLOPI3K/AktOuter membraneCytochrome cFeatures of apoptosisSpecific PI3K inhibitor LY294002PI3K inhibitor LY294002K inhibitor LY294002Mitochondrial translocationMitochondrial releaseMitochondrial membraneVulnerable CA1 pyramidal cellsLarge conductance channelBad translocationInhibitor LY294002PI3KNeuronal deathChannel activityVivo 1 hDIABLOMitochondriaAktTranslocationBcl
2007
Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission
Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA. Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission. Journal Of Neurophysiology 2007, 99: 1515-1522. PMID: 18160428, PMCID: PMC2836590, DOI: 10.1152/jn.00598.2007.Peer-Reviewed Original ResearchConceptsMitochondrial outer membraneEndogenous Bcl-xLMitochondrial channel activityBcl-xLInhibitor ABT-737ABT-737Outer membraneBcl-xL.Pro-apoptotic cleavage productRecombinant Bcl-xLChannel activityBcl-xL proteinSynaptic functionDual roleGenetic toolsDomain pocketSynaptic transmissionSynaptic activityGiant presynaptic terminalEquivalent modificationEndogenous proteolysisRepetitive synaptic activityBH3Cleavage productsProteinHypoxia increases BK channel activity in the inner mitochondrial membrane
Gu XQ, Siemen D, Parvez S, Cheng Y, Xue J, Zhou D, Sun X, Jonas EA, Haddad GG. Hypoxia increases BK channel activity in the inner mitochondrial membrane. Biochemical And Biophysical Research Communications 2007, 358: 311-316. PMID: 17481584, DOI: 10.1016/j.bbrc.2007.04.110.Peer-Reviewed Original Research
2006
Zinc-Dependent Multi-Conductance Channel Activity in Mitochondria Isolated from Ischemic Brain
Bonanni L, Chachar M, Jover-Mengual T, Li H, Jones A, Yokota H, Ofengeim D, Flannery RJ, Miyawaki T, Cho CH, Polster BM, Pypaert M, Hardwick JM, Sensi SL, Zukin RS, Jonas EA. Zinc-Dependent Multi-Conductance Channel Activity in Mitochondria Isolated from Ischemic Brain. Journal Of Neuroscience 2006, 26: 6851-6862. PMID: 16793892, PMCID: PMC4758341, DOI: 10.1523/jneurosci.5444-05.2006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternBrain IschemiaCaspasesChelating AgentsDiagnostic ImagingDose-Response Relationship, DrugEthylenediaminesIon Channel GatingIon ChannelsMaleMembrane PotentialsMicroscopy, Electron, TransmissionMitochondriaNADPatch-Clamp TechniquesRatsRats, Sprague-DawleySynaptosomesXanthenesZinc
2005
Actions of BAX on Mitochondrial Channel Activity and on Synaptic Transmission
Jonas EA, Hardwick JM, Kaczmarek LK. Actions of BAX on Mitochondrial Channel Activity and on Synaptic Transmission. Antioxidants & Redox Signaling 2005, 7: 1092-1100. PMID: 16115013, DOI: 10.1089/ars.2005.7.1092.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBcl-2-Associated X ProteinBcl-X ProteinCell MembraneElectrophysiologyIntracellular MembranesLiposomesLoligoMitochondriaMultigene FamilyNeurotransmitter AgentsPatch-Clamp TechniquesPeptidesPresynaptic TerminalsProtein Structure, TertiarySynapsesSynaptic TransmissionTime FactorsConceptsMitochondrial membraneBcl-2 family proteins BaxCell deathOuter mitochondrial membraneAction of BaxMitochondrial channel activityChannel activityNormal physiological settingsAntiapoptotic Bcl-xL proteinBcl-xL proteinDeath channelMitochondrial architectureMitochondrial channelsProapoptotic fragmentsLarge conductance channelPresynaptic terminalsBcl-xL.Proapoptotic proteinsAlternative functionsProtein BaxPhysiological settingsPhysiological roleSynaptic transmissionBaxNeurotransmitter releaseOligomeric Bax Is a Component of the Putative Cytochrome c Release Channel MAC, Mitochondrial Apoptosis-induced Channel
Dejean LM, Martinez-Caballero S, Guo L, Hughes C, Teijido O, Ducret T, Ichas F, Korsmeyer SJ, Antonsson B, Jonas EA, Kinnally KW. Oligomeric Bax Is a Component of the Putative Cytochrome c Release Channel MAC, Mitochondrial Apoptosis-induced Channel. Molecular Biology Of The Cell 2005, 16: 2424-2432. PMID: 15772159, PMCID: PMC1087246, DOI: 10.1091/mbc.e04-12-1111.Peer-Reviewed Original ResearchConceptsMitochondrial apoptosis-induced channelOligomeric BaxBcl-2 family proteinsHeLa cellsBcl-2-overexpressing cellsCytochrome cChannel activityMAC activityIntrinsic apoptotic pathwayApoptotic cellsFamily proteinsIntrinsic apoptosisApoptotic pathwaySingle-channel behaviorMitochondriaBaxBax antibodiesMean conductanceBakUntreated cellsRelease channelProteinApoptosisCellsTranslocation
2004
Exposure to Hypoxia Rapidly Induces Mitochondrial Channel Activity within a Living Synapse*
Jonas EA, Hickman JA, Hardwick JM, Kaczmarek LK. Exposure to Hypoxia Rapidly Induces Mitochondrial Channel Activity within a Living Synapse*. Journal Of Biological Chemistry 2004, 280: 4491-4497. PMID: 15561723, DOI: 10.1074/jbc.m410661200.Peer-Reviewed Original ResearchConceptsMitochondrial channel activityMitochondrial membraneChannel activityBcl-xLBcl-2 family proteinsPro-apoptotic fragmentsOuter mitochondrial membraneTrigger cell deathZ-VAD-FMKBenzyloxycarbonyl-VADFamily proteinsSynaptic responsesMulticonductance channelLarge conductance channelFluoromethyl ketoneCell deathMinutes of hypoxiaResponses of neuronsNeuronal functionSquid giant synapseSynaptic mitochondriaEarly eventsSynaptic functionHypoxic conditionsNeuronal deathProapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals
Jonas EA, Hickman JA, Chachar M, Polster BM, Brandt TA, Fannjiang Y, Ivanovska I, Basañez G, Kinnally KW, Zimmerberg J, Hardwick JM, Kaczmarek LK. Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 13590-13595. PMID: 15342906, PMCID: PMC518799, DOI: 10.1073/pnas.0401372101.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBcl-X ProteinDecapodiformesElectric ConductivityEndopeptidasesHypoxiaIon ChannelsLiposomesMitochondriaNADPatch-Clamp TechniquesPorinsPresynaptic TerminalsProtein Processing, Post-TranslationalProto-Oncogene Proteins c-bcl-2Sequence DeletionVoltage-Dependent Anion ChannelsConceptsBcl-xLMitochondrial channelsDeath pathwaysMitochondrial membraneBcl-xL.Proapoptotic Bcl-2 family proteinsVoltage-dependent anion channelBcl-2 family proteinsOuter mitochondrial membraneCell death pathwaysHydrophobic C-terminusBcl-xL proteinAntiapoptotic Bcl-xLNeuronal death pathwaysDeath stimuliBH3 domainFamily proteinsSquid presynaptic terminalsMammalian cellsC-terminusAnion channelMitochondriaChannel activityOpposite effectHealthy neuronsRegulation of Synaptic Transmission by Mitochondrial Ion Channels
Jonas E. Regulation of Synaptic Transmission by Mitochondrial Ion Channels. Journal Of Bioenergetics And Biomembranes 2004, 36: 357-361. PMID: 15377872, DOI: 10.1023/b:jobb.0000041768.11006.90.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBcl-X ProteinCell HypoxiaCell MembraneDecapodiformesElectric ConductivityHomeostasisHumansIon Channel GatingIon ChannelsMembrane PotentialsMitochondriaMitochondrial ProteinsNeuronsOxidative StressPorinsProto-Oncogene Proteins c-bcl-2Synaptic TransmissionVoltage-Dependent Anion ChannelsConceptsMitochondrial outer membraneVoltage-dependent anion channelOuter membraneBcl-xLSynaptic transmissionChannel activityNeuronal presynaptic terminalsMitochondrial ion channelsProteolytic fragmentsBcl-xL proteinRelease of ATPIon channel activityPresynaptic terminalsRapid onsetSynaptic functionNeurotransmitter releaseBcl-xL.Anion channelNeurotransmitter secretionPrevents cleavageHypoxiaIon channelsProtease inhibitorsLarge conductanceMitochondria
2003
Modulation of Synaptic Transmission by the BCL-2 Family Protein BCL-xL
Jonas EA, Hoit D, Hickman JA, Brandt TA, Polster BM, Fannjiang Y, McCarthy E, Montanez MK, Hardwick JM, Kaczmarek LK. Modulation of Synaptic Transmission by the BCL-2 Family Protein BCL-xL. Journal Of Neuroscience 2003, 23: 8423-8431. PMID: 12968005, PMCID: PMC6740692, DOI: 10.1523/jneurosci.23-23-08423.2003.Peer-Reviewed Original ResearchConceptsBcl-2 family proteinsProtein Bcl-xLBcl-xLFamily proteinsMitochondrial membranePro-apoptotic cleavage productRecombinant Bcl-xLBcl-xL proteinMitochondrial calcium uptakePresynaptic terminalsInfluences synaptic transmissionCell deathGiant presynaptic terminalSynaptic transmissionChannel activityProteinSquid stellate ganglionMitochondriaCleavage productsSynaptic stabilityAdult brainPostsynaptic responsesCalcium uptakeMembranePatch pipette
1999
Prolonged Activation of Mitochondrial Conductances During Synaptic Transmission
Jonas E, Buchanan J, Kaczmarek L. Prolonged Activation of Mitochondrial Conductances During Synaptic Transmission. Science 1999, 286: 1347-1350. PMID: 10558987, DOI: 10.1126/science.286.5443.1347.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsCalciumCalcium ChannelsDecapodiformesElectric ConductivityElectric StimulationIntracellular MembranesIon ChannelsIon TransportMicroscopy, ElectronMitochondriaPatch-Clamp TechniquesPorinsPresynaptic TerminalsSynaptic TransmissionTime FactorsVoltage-Dependent Anion ChannelsConceptsChannel activityIon channel activityMitochondrial membraneOnly organellesIntracellular organellesIntact cellsIon channelsMitochondriaOrganellesLarge conductanceTens of secondsPresynaptic terminalsIon transportSynaptic transmissionSynaptic stimulationConductanceElectron microscopyPatch-clamp techniqueMembraneActivityCellsActivationSquidStimulation