2024
Mitochondrial ATP synthase as a novel therapeutic drug target in neurodegenerative and ischemic heart diseases
Kumar A, da Fonseca Rezende e Mello J, Wu Y, Mezghani I, Smith E, Mnatsakanyan N. Mitochondrial ATP synthase as a novel therapeutic drug target in neurodegenerative and ischemic heart diseases. Biochimica Et Biophysica Acta (BBA) - Bioenergetics 2024, 1865: 149307. DOI: 10.1016/j.bbabio.2024.149307.Peer-Reviewed Original Research
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
2021
The nucleotide binding affinities of two critical conformations of Escherichia coli ATP synthase
Li Y, Valdez NA, Mnatsakanyan N, Weber J. The nucleotide binding affinities of two critical conformations of Escherichia coli ATP synthase. Archives Of Biochemistry And Biophysics 2021, 707: 108899. PMID: 33991499, PMCID: PMC8278868, DOI: 10.1016/j.abb.2021.108899.Peer-Reviewed Original ResearchConceptsATP synthaseCritical conformationEscherichia coli ATP synthaseRotary catalytic mechanismCatalytic dwell stateCatalytic mechanismAerobic energy metabolismΓ subunitCysteine mutationsTryptophan fluorescenceDwell stateDisulfide bondsEnergetic functionEnergy metabolismCatalytic siteSynthaseCatalytic dwellAffinity changesATPEnzymeAffinityConformationSubunitsMutationsSites
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 potential
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 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 culturesATP 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
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
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
2009
The Role of the βDELSEED-loop of ATP Synthase*
Mnatsakanyan N, Krishnakumar AM, Suzuki T, Weber J. The Role of the βDELSEED-loop of ATP Synthase*. Journal Of Biological Chemistry 2009, 284: 11336-11345. PMID: 19246448, PMCID: PMC2670139, DOI: 10.1074/jbc.m900374200.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAmino Acid SequenceATP Synthetase ComplexesBacillusBinding SitesCell MembraneEscherichia coliMitochondrial Proton-Translocating ATPasesMolecular ConformationMolecular Sequence DataMutationNucleotidesPhosphorylationProtein Structure, TertiarySequence Homology, Amino AcidConceptsWild-type enzymeATP synthaseDELSEED-loopDeletion mutantsATP hydrolysisUnique rotational mechanismTransmembrane proton gradientHelix motifRate-limiting catalytic stepTerminal domainFunctional analysisMutantsBeta subunitMembrane vesiclesATP synthesisProton gradientAmino acidsLow abundanceCatalytic stepMechanochemical couplingCatalytic siteSynthaseChemical energyEnzymeMembrane preparations
2002
F0 Cysteine, bCys21, in the Escherichia coli ATP Synthase Is Involved in Regulation of Potassium Uptake and Molecular Hydrogen Production in Anaerobic Conditions
Mnatsakanyan N, Bagramyan K, Vassilian A, Nakamoto RK, Trchounian A. F0 Cysteine, bCys21, in the Escherichia coli ATP Synthase Is Involved in Regulation of Potassium Uptake and Molecular Hydrogen Production in Anaerobic Conditions. Bioscience Reports 2002, 22: 421-430. PMID: 12516783, DOI: 10.1023/a:1020918125453.Peer-Reviewed Original ResearchConceptsEscherichia coli ATP synthaseATP synthaseMembrane vesiclesMolecular hydrogen productionATP-dependent increaseF0 sectorF1 sectorAnaerobic conditionsCysteine replacementMutant enzymesFermentative conditionsATP hydrolysisSingle cysteineAccessible thiol groupsPotassium uptakeWhole cellsB subunitCysteineVesiclesSynthaseThiol groupsCellsProtoplastsSubunitsUptake