Nelli Mnatsakanyan, PhD
Assistant Professor AdjunctCards
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About
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Assistant Professor Adjunct
Biography
Dr. Mnatsakanyan is currently an Associate Professor at the Pennsylvania State University College of Medicine. She obtained her Ph.D. from Yerevan State University and performed her postdoctoral work at Texas Tech University Health Sciences Center. As a postdoctoral fellow, she studied the catalytic mechanism of the ATP synthase and characterized an important structural unit, beta DELSEED loop region of the ATP synthase that couples ATP synthesis with subunit rotation. Dr. Mnatsakanyan's current research focuses on understanding the molecular mechanism and regulation of the enigmatic cell death channel located in the mitochondrial ATP synthase and its role in mitochondrial permeability transition (mPTP). The goals in her lab are threefold: 1) Identify and structurally characterize the molecular components of mPTP by using cryo-electron microscopy and cryo-electron tomography. 2) Functionally characterize the ATP synthase leak channel and its regulation by using electrophysiology techniques, patch-clamp and planar lipid bilayer recordings. 3) Generate CRISPR/Cas9-edited mice with a low probability of ATP synthase leak channel/mPTP opening and introduce these mutations in transgenic Alzheimer's disease (AD) mice to study if they will protect the mice from the onset of AD-like features. These studies may lead to the structure-based drug design of specific therapeutic compounds for the treatment of mPTP-related neurodegenerative disorders, aging and cancer.
Appointments
Endocrinology
Assistant Professor AdjunctPrimary
Other Departments & Organizations
Education & Training
- PhD
- Yerevan State University, Biophysics (2003)
- MS
- Yerevan State University (1999)
- BS
- Yerevan State University (1999)
Research
Overview
Medical Subject Headings (MeSH)
ORCID
0000-0001-5363-7409
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Elizabeth Jonas, MD
Pawel Licznerski, PhD
Marc C Llaguno, PhD
Kambiz Alavian, PhD
Mitochondria
ATP Synthetase Complexes
Neurodegenerative Diseases
Alpha7 Nicotinic Acetylcholine Receptor
Publications
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 ResearchProtonation-dependent ion flux in a mitochondrial leak channel
Wang Q, Mnatsakanyan N, Jonas E, Pias S. Protonation-dependent ion flux in a mitochondrial leak channel. Biophysical Journal 2024, 123: 522a. DOI: 10.1016/j.bpj.2023.11.3159.Peer-Reviewed Original ResearchCryo-electron microscopy studies reveal the inactivation mechanism of ATP synthase leak channel and its contribution to mitochondrial permeability transition
Kumar A, da Fonseca Rezende e Mello J, Wu Y, Morris D, Mnatsakanyan N. Cryo-electron microscopy studies reveal the inactivation mechanism of ATP synthase leak channel and its contribution to mitochondrial permeability transition. Biophysical Journal 2024, 123: 164a. DOI: 10.1016/j.bpj.2023.11.1100.Peer-Reviewed Original ResearchA curious study on the ATP synthase C-ring: A voltage-sensing leak channel
Nguyen J, Chan C, Layton J, Mnatsakanyan N, Singharoy A. A curious study on the ATP synthase C-ring: A voltage-sensing leak channel. Biophysical Journal 2024, 123: 249a. DOI: 10.1016/j.bpj.2023.11.1573.Peer-Reviewed Original Research
2022
Fluid shear stress enhances proliferation of breast cancer cells via downregulation of the c-subunit of the F1FO ATP synthase
Park HA, Brown SR, Jansen J, Dunn T, Scott M, Mnatsakanyan N, Jonas EA, Kim Y. Fluid shear stress enhances proliferation of breast cancer cells via downregulation of the c-subunit of the F1FO ATP synthase. Biochemical And Biophysical Research Communications 2022, 632: 173-180. PMID: 36209586, PMCID: PMC10024463, DOI: 10.1016/j.bbrc.2022.09.084.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMitochondrial 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMitochondrial 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 ResearchMeSH Keywords and ConceptsConceptsATP 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsFragile 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMitochondrial 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMitochondrial 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 phenomenon
Academic Achievements & Community Involvement
activity "Biomedicine & Pharmacotherapy" Elsevier Journal
Journal ServiceAssociate EditorDetailsAssociate Editor2018 - Presentactivity Society of Neuroscience
Professional OrganizationsMemberDetailsMember09/01/2011 - Presentactivity Biophysical Society
Professional OrganizationsMemberDetailsMember09/01/2011 - Presentactivity "Bioenergetics, Mitochondria and Metabolism" Subgroup, Biophysical Society
Professional OrganizationsMemberDetailsMember2015 - Presentactivity Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART)
Professional OrganizationsMemberDetailsMember04/01/2019 - Present
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Media
- The single-particle cryo-EM analysis was used to assess the oligomeric state of purified ATP synthase after reconstitution into a small unilamellar vesicle.
- Photomicrographic image during a patch-clamp recording showing the patch-clamp pipette sealed onto the ATP synthase reconstituted giant unilamellar vesicle. Scale bar, 50 μm.