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 consumptionIdentity, 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
2021
Mitochondria: powerhouses of presynaptic plasticity
Subramanian S, Jonas EA. Mitochondria: powerhouses of presynaptic plasticity. The Journal Of Physiology 2021, 599: 1363-1364. PMID: 33428213, PMCID: PMC7942974, DOI: 10.1113/jp281040.Peer-Reviewed Original Research
2020
ATP 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 outgrowthDopamine fuels its own release
Chen R, Jonas EA. Dopamine fuels its own release. Nature Neuroscience 2019, 23: 1-2. PMID: 31844312, DOI: 10.1038/s41593-019-0563-4.Peer-Reviewed Original ResearchParkinson’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
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 mechanismsPhylogenetic Profiling of Mitochondrial Proteins and Integration Analysis of Bacterial Transcription Units Suggest Evolution of F1Fo ATP Synthase from Multiple Modules
Niu Y, Moghimyfiroozabad S, Safaie S, Yang Y, Jonas EA, Alavian KN. Phylogenetic Profiling of Mitochondrial Proteins and Integration Analysis of Bacterial Transcription Units Suggest Evolution of F1Fo ATP Synthase from Multiple Modules. Journal Of Molecular Evolution 2017, 85: 219-233. PMID: 29177973, PMCID: PMC5709465, DOI: 10.1007/s00239-017-9819-3.Peer-Reviewed Original ResearchConceptsBacterial transcription unitsF1Fo-ATP synthaseHuman mitochondrial proteinsTranscription unitATP synthaseMitochondrial proteinsPhylogenetic profilesF-type ATP synthaseATP synthase genesSeparate transcription unitsKingdoms of lifeATP synthase complexPeripheral stalk subunitsC subunit ringComplex evolutionary processesAncestral modulesPhylogenetic profilingModular evolutionSynthase complexBacterial genomesUniversal enzymeSynthase geneBacterial classesIndependent assemblyΑ3β3 hexamer
2015
Cell 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
An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore
Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA, Licznerski P, Li H, Nabili P, Hockensmith K, Graham M, Porter GA, Jonas EA. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 10580-10585. PMID: 24979777, PMCID: PMC4115574, DOI: 10.1073/pnas.1401591111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCell DeathHEK293 CellsHumansIon Channel GatingIon ChannelsLiposomesMitochondriaMitochondrial Membrane Transport ProteinsMitochondrial MembranesMitochondrial Permeability Transition PoreMutationProtein ConformationProtein SubunitsProton-Translocating ATPasesRatsReactive Oxygen SpeciesConceptsMitochondrial PT poreF1Fo-ATP synthaseATP synthasePermeability transitionCell deathCellular metabolic efficiencyInner mitochondrial membrane permeabilityOxygen species-induced cell deathC subunit ringATP synthase F1Mitochondrial membrane permeabilityMitochondrial permeability transitionC subunitPT poreTight regulationATP productionMolecular identitySingle-channel conductanceChannel closureLeak channelsMPTP openingMetabolic efficiencyMembrane permeabilityHealthy cellsOsmotic shifts
2013
A Bcl-xL–Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis
Li H, Alavian KN, Lazrove E, Mehta N, Jones A, Zhang P, Licznerski P, Graham M, Uo T, Guo J, Rahner C, Duman RS, Morrison RS, Jonas EA. A Bcl-xL–Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis. Nature Cell Biology 2013, 15: 773-785. PMID: 23792689, PMCID: PMC3725990, DOI: 10.1038/ncb2791.Peer-Reviewed Original ResearchConceptsBcl-xLVesicle retrievalProtein-protein interactionsClathrin-coated pitsProtein Bcl-xLCalmodulin-dependent mannerRecruitment of vesiclesNeurotransmitter releaseDepletion of Drp1GTPase Drp1Vesicle endocytosisEndocytic vesiclesMembrane dynamicsPlasma membraneClathrin complexMutagenesis studiesPresynaptic plasticityMitochondrial ATPATP availabilityReserve poolDrp1EndocytosisVesiclesHippocampal neuronsComplexesF1FO ATPase vesicle preparation and technique for performing patch clamp recordings of submitochondrial vesicle membranes.
Sacchetti S, Alavian KN, Lazrove E, Jonas EA. F1FO ATPase vesicle preparation and technique for performing patch clamp recordings of submitochondrial vesicle membranes. Journal Of Visualized Experiments 2013, e4394. PMID: 23685483, PMCID: PMC3676267, DOI: 10.3791/4394.Peer-Reviewed Original ResearchConceptsF1Fo-ATP synthaseATP synthaseF1Fo-ATPaseSubmitochondrial vesiclesNecrotic cell deathPro-apoptotic factorsCell deathOuter membraneBcl-2 family proteinsMitochondrial outer membraneImportant cellular functionsOuter membrane ruptureImportant mitochondrial functionsRole of mitochondriaMediation of signalsMitochondrial permeability transition poreProduction of ATPApoptotic cell deathPermeability transition poreInner membrane poreCellular functionsFamily proteinsInner membraneOxidative phosphorylationBeta subunitPINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage
Arena G, Gelmetti V, Torosantucci L, Vignone D, Lamorte G, De Rosa P, Cilia E, Jonas EA, Valente EM. PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage. Cell Death & Differentiation 2013, 20: 920-930. PMID: 23519076, PMCID: PMC3679455, DOI: 10.1038/cdd.2013.19.Peer-Reviewed Original ResearchConceptsBcl-xLMitochondrial depolarizationCell deathPro-autophagic protein Beclin-1Autosomal recessive Parkinson's diseaseBeclin-1Recessive Parkinson's diseaseAnti-apoptotic proteinsXL interactionMitochondrial kinaseProtein Beclin 1Mitochondrial traffickingMitochondrial homeostasisMitophagy pathwayBcl-xL.PINK1Functional linkCell survivalPathogenesis of PDNovel mechanismPINK1 genePathwayCleavageMitophagyParkinson's disease
2012
Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency
Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Mariggio MA, Onofrj M, Thomas A, Li H, Mangold JE, Signore AP, DeMarco U, Demady DR, Nabili P, Lazrove E, Smith PJ, Gribkoff VK, Jonas EA. Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Research 2012, 1446: 1-11. PMID: 22364637, PMCID: PMC3746080, DOI: 10.1016/j.brainres.2012.01.046.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAdrenergic beta-AntagonistsAnalysis of VarianceAnimalsBiophysical PhenomenaBrainCell SurvivalCells, CulturedCyclosporineDose-Response Relationship, DrugEnergy MetabolismEnzyme InhibitorsHumansMaleMembrane Potential, MitochondrialMiceMitochondriaMitochondrial MembranesNeuroblastomaNeuronsOligopeptidesOxygen ConsumptionPatch-Clamp TechniquesPropranololRatsRats, Sprague-DawleyConceptsAmyotrophic lateral sclerosisParkinson's diseaseRisk of deathChronic neurological disorderLateral sclerosisInefficient energy productionNeurological disordersMitochondrial dysfunctionMembrane currentsDiseaseCellular energy productionDysfunctional mitochondriaCellular stressSclerosisDysfunctionDexpramipexoleInjuryNeurons
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 cristaeBcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase
Alavian KN, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli SM, Mariggio MA, Rahner C, McNay E, Shore GC, Smith PJ, Hardwick JM, Jonas EA. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nature Cell Biology 2011, 13: 1224-1233. PMID: 21926988, PMCID: PMC3186867, DOI: 10.1038/ncb2330.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBcl-2 Homologous Antagonist-Killer ProteinBcl-2-Associated X ProteinBcl-X ProteinBiphenyl CompoundsCarbonyl Cyanide p-TrifluoromethoxyphenylhydrazoneCells, CulturedEnergy MetabolismEnzyme InhibitorsHippocampusHydrolysisMembrane Potential, MitochondrialMitochondriaMitochondrial MembranesMitochondrial Proton-Translocating ATPasesNeuronsNitrophenolsOligomycinsOxygen ConsumptionPatch-Clamp TechniquesPiperazinesProton IonophoresRatsRecombinant Fusion ProteinsRNA InterferenceSulfonamidesSynapsesTime FactorsTransfectionConceptsBcl-xLSynthase complexATP synthaseMitochondrial F1Fo-ATP synthaseAnti-apoptotic BCL2 family proteinsF1Fo-ATP synthaseATP synthase complexF1FO-ATPase activityBcl-xL activityATPase activityBcl-xL proteinBCL2 family proteinsEndogenous Bcl-xLPresence of ATPFamily proteinsATPase complexNormal neuronal functionMembrane leak conductanceSubmitochondrial vesiclesΒ-subunitProtect cellsGenetic inhibitionMitochondrial efficiencyF1FoApoptotic molecules
2009
Molecular participants in mitochondrial cell death channel formation during neuronal ischemia
Jonas EA. Molecular participants in mitochondrial cell death channel formation during neuronal ischemia. Experimental Neurology 2009, 218: 203-212. PMID: 19341732, PMCID: PMC2710418, DOI: 10.1016/j.expneurol.2009.03.025.Peer-Reviewed Original ResearchConceptsBcl-2 family proteinsCell deathFamily proteinsInner membraneOuter membraneIon channelsMolecular participantsNumerous cellular processesMitochondrial ion channelsComplex of proteinsSpecialized physiological functionsMembrane compartmentalizationIon channel complexCellular processesPhysiological functionsIon channel conductanceCytosolic metabolitesChannel complexProteinMembrane potentialChannel formationMembraneChannel conductanceSynaptic transmissionVDAC