2024
Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment
Sun F, Wang H, Wu J, Quraishi I, Zhang Y, Pedram M, Gao B, Jonas E, Nguyen V, Wu S, Mabrouk O, Jafar-nejad P, Kaczmarek L. Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment. Biomolecules 2024, 14: 1397. DOI: 10.3390/biom14111397.Peer-Reviewed Original ResearchWild-type miceKO miceSpectrum of epilepsy syndromesAntisense oligonucleotidesGain-of-function variantsAntisense oligonucleotide treatmentEpileptic phenotypePotassium channelsKCNT1Molecular profilingOligonucleotide treatmentAnimal modelsEpilepsy syndromesC-terminal mutationsIncreased expressionCerebral cortexMiceExpression of multiple proteinsComprehensive proteomic analysisDisease modelsCortical mitochondriaMolecular differencesDensity of mitochondrial cristaeMitochondrial membraneTreatment
2023
Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions
Bernardi P, Gerle C, Halestrap A, Jonas E, Karch J, Mnatsakanyan N, Pavlov E, Sheu S, Soukas A. Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions. Cell Death & Differentiation 2023, 30: 1869-1885. PMID: 37460667, PMCID: PMC10406888, DOI: 10.1038/s41418-023-01187-0.Peer-Reviewed Original ResearchConceptsMitochondrial permeability transition poreMitochondrial permeability transitionAdenine nucleotide translocasePermeability transition poreATP synthase dimersTransition poreInner mitochondrial membrane permeabilityC subunit ringOuter mitochondrial membraneMitochondrial membrane permeabilityDeath of cellsMPTP openingNecrotic cell deathMitochondrial membraneNucleotide translocaseTransient mPTP openingMitochondrial bioenergeticsSub-conductance statesMolecular identityPermeability transitionCell deathPhysiological roleNon-selective channelsDiscovery decadesMembrane permeability
2020
Oxidative stress battles neuronal Bcl-xL in a fight to the death
Park HA, Broman K, Jonas EA. Oxidative stress battles neuronal Bcl-xL in a fight to the death. Neural Regeneration Research 2020, 16: 12-15. PMID: 32788441, PMCID: PMC7818872, DOI: 10.4103/1673-5374.286946.Peer-Reviewed Original ResearchBcl-xLMitochondrial membraneBcl-xL.BCL2 proteinFO ATP synthaseBcl-XL bindsPost-translational phosphorylationOxidative stressBcl-x geneSynaptic vesicle recyclingActivation of caspasesPro-survival proteinsMitochondrial ATP productionAnti-apoptotic roleUndergoes proteolytic cleavageMultiprotein complexesATP synthaseTranscription factorsVesicle recyclingBCL2 familyApoptotic signalingKey regulatorPhysiological processesAlters formationATP production
2019
Vitamin E Prevents ΔN-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19)
Park H, Mnatsakanyan N, Broman K, Jonas E. Vitamin E Prevents ΔN-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19). Current Developments In Nutrition 2019, 3: nzz052.p14-024-19. PMCID: PMC6574370, DOI: 10.1093/cdn/nzz052.p14-024-19.Peer-Reviewed Original ResearchBcl-xL.Bcl-xLPrimary hippocampal neuronsMitochondrial dysfunctionRedox statusBcl-xL protein levelsCaspase-dependent cleavageAnti-apoptotic Bcl-xLMitochondrial redox statusPro-survival proteinsNeuronal deathMitochondrial oxidative stressHippocampal neuronsOxidative stressReactive oxygen species formationMitochondrial membraneCaspase activitySubsequent oxidative stressMitochondrial potentialMitochondrial functionNeuronal energy metabolismOxygen species formationDependent cleavageOxidative stress productionEnergy metabolism
2017
Inhibition 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 toxicityThe Mitochondrial Permeability Transition Pore: Molecular Structure and Function in Health and Disease
Jonas E, Porter G, Beutner G, Mnatsakanyan N, Park H, Mehta N, Chen R, Alavian K. The Mitochondrial Permeability Transition Pore: Molecular Structure and Function in Health and Disease. Biological And Medical Physics, Biomedical Engineering 2017, 69-105. DOI: 10.1007/978-3-319-55539-3_3.Peer-Reviewed Original ResearchMitochondrial permeability transition porePermeability transition poreCell deathTransition poreMitochondrial inner membraneInner mitochondrial membraneC subunitATP synthaseInner membraneOuter membraneMitochondrial membraneCardiac developmentRegulatory mechanismsOxidative phosphorylationATP productionMitochondrial functionMolecular componentsMitochondrial efficiencyOsmotic dysregulationCell functionLarge conductanceRecent findingsPersistent openingMembraneIon transport
2016
Physiological 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
The Mitochondrial Permeability Transition Pore, the c‐Subunit of the F1Fo ATP Synthase, Cellular Development, and Synaptic Efficiency
Jonas E, Porter G, Beutner G, Mnatsakanyan N, Alavian K. The Mitochondrial Permeability Transition Pore, the c‐Subunit of the F1Fo ATP Synthase, Cellular Development, and Synaptic Efficiency. 2015, 31-64. DOI: 10.1002/9781119017127.ch2.Peer-Reviewed Original ResearchMitochondrial permeability transition poreMitochondrial membrane permeabilizationPermeability transition poreATP synthaseC subunitCell deathOuter mitochondrial membrane permeabilizationTransition poreF1Fo-ATP synthaseInner mitochondrial membraneMembrane channel activityMitochondrial permeability transitionMetabolic plasticityPT poreOuter membraneCellular developmentMembrane permeabilizationMitochondrial membraneRegulatory mechanismsOxidative phosphorylationAdenosine triphosphate (ATP) productionMitochondrial functionPermeability transitionMolecular componentsTriphosphate productionCell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase
Jonas EA, Porter GA, Beutner G, Mnatsakanyan N, Alavian KN. Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase. Pharmacological Research 2015, 99: 382-392. PMID: 25956324, PMCID: PMC4567435, DOI: 10.1016/j.phrs.2015.04.013.BooksConceptsMitochondrial permeability transition poreATP synthaseC subunitCell deathF1Fo-ATP synthaseInner mitochondrial membranePermeability transition poreMitochondrial permeability transitionOuter membraneMitochondrial membraneRegulatory mechanismsOxidative phosphorylationATP productionTransition poreMitochondrial functionPermeability transitionMolecular componentsOsmotic dysregulationLarge conductancePathological roleRecent findingsPersistent openingSynthaseIon transportMembrane
2014
The Mitochondrial Complex V–Associated Large-Conductance Inner Membrane Current Is Regulated by Cyclosporine and Dexpramipexole
Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Li H, Signore AP, Smith PJ, Gribkoff VK, Jonas EA. The Mitochondrial Complex V–Associated Large-Conductance Inner Membrane Current Is Regulated by Cyclosporine and Dexpramipexole. Molecular Pharmacology 2014, 87: 1-8. PMID: 25332381, PMCID: PMC4279080, DOI: 10.1124/mol.114.095661.Peer-Reviewed Original ResearchConceptsF1Fo-ATP synthaseInner mitochondrial membraneATP synthaseMitochondrial permeability transition poreSubmitochondrial vesiclesOligomycin sensitivity-conferring protein subunitMitochondrial membraneMitochondrial F1Fo-ATP synthaseMitochondrial matrix calciumFunctional conformational changesCellular energy productionHydrolysis of ATPPermeability transition poreC subunitIon conductanceATP/ADPProtein subunitsEnzyme complexOxidative phosphorylationConformational changesTransition poreComplex VLeak conductanceMatrix calciumEnergy production
2011
Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential
Chen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM, Cheng WC, Qi B, Li H, Alavian KN, Dayhoff-Brannigan M, Zou S, Pineda FJ, O'Rourke B, Ko YH, Pedersen PL, Kaczmarek LK, Jonas EA, Hardwick JM. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. Journal Of Cell Biology 2011, 195: 263-276. PMID: 21987637, PMCID: PMC3198165, DOI: 10.1083/jcb.201108059.Peer-Reviewed Original ResearchConceptsMitochondrial membrane potentialMitochondrial membraneMitochondrial ATP synthase β-subunitATP synthase β subunitBcl-2 family proteinsOuter membrane permeabilizationInner mitochondrial membrane potentialMembrane potentialMitochondrial energetic capacityOuter mitochondrial membraneSynthase β subunitInner mitochondrial membraneInner membrane potentialATP synthaseFamily proteinsBiochemical approachesGenetic evidenceEndogenous BclMembrane permeabilizationCellular resourcesΒ-subunitBcl-xLMitochondrial energeticsEnergetic capacityMitochondrial cristae
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
Hypoxia 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 release
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 neurons
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