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Elizabeth Jonas, MD

Professor of Internal Medicine (Endocrinology) and Neuroscience

Contact Information

Elizabeth Jonas, MD

Mailing Address

  • Endocrinology

    PO Box 208020, 333 Cedar Street

    New Haven, CT 06520-8056

    United States

Research Summary

Some of the features of neuronal synaptic transmission that can be modified over the short and long term include changes in presynaptic calcium levels, changes in vesicle numbers and probability of release, and alterations in postsynaptic receptor numbers and function. Such variations account in part for the synaptic plasticity that may underlie learning and memory. Alterations in levels of activity at the synapse require energy and other mitochondrial activities, and therefore mitochondria influence synaptic events by changes in mitochondrial targeting, shape, size and metabolic efficiency. Bcl-2 family proteins, by their actions at mitochondrial membranes, normally play an important role in cell death at the soma, but also strengthen or weaken synaptic connections. Mitochondria also regulate key metabolic events including protein and lipid synthesis required for synaptic plasticity.

Thus the actions of mitochondria at synaptic sites position these organelles to influence physiological and pathological changes in the brain. In neurodegenerative diseases, proteins that control mitochondrial ion channel activity may be key in deciding whether a synapse will live or die, and thereby whether a neuron will survive or undergo untimely death. In neurodevelopmental disease, mitochondrial metabolic changes are required for critical periods in brain and synaptic development.

Specialized Terms: Brain ischemia; Neurodegeneration; Neurodevelopment; Parkinson's Disease; Fragile X Disorder; Autism; Mitochondrial ion channels; Cell death; synaptic transmission; synaptic plasticity; ATP synthase; mitochondrial permeability transition pore (mPTP).

Extensive Research Description

  • Role of ATP synthase in prevention of cardiac and brain ischemia: Mitochondrial ATP synthase has been shown recently to be vital not only for cellular energy production but also for energy dissipation and cell death. We identified and characterized a large non-selective uncoupling channel within the ATP synthase c-subunit ring, the persistent opening of which initiates cell death. We have growing evidence for its crucial role in mitochondrial permeability transition (mPT), the opening of a cell death channel that regulates neuronal death during ischemia and neurodegeneration. We have found that the c-ring channel is also required for certain critical periods in brain development, and that normal closing of the channel is required for normal brain and synaptic development. We have now purified ATP synthase from porcine heart mitochondria and performed single-channel studies.
  • Structural studies of the ATP synthase c-ring pore: Excised proteoliposome patch-clamp recordings demonstrate that highly pure and fully assembled ATP synthase monomers form large conductance, Ca2+-sensitive and voltage-gated channels. We have confirmed the monomeric state of ATP synthase by cryo-electron microscopy studies of ATP synthase reconstituted into proteoliposomes. We have also heterologously overexpressed and purified human ATP synthase c-subunit fromHEK-293 cells and from E. coli plasma membranes. C-subunit ring purified using this technique forms large conductance channels. C-ring channel is gated by polar amino acid residues situated at the mouth of the pore and by the hydrophilic F1 portion of ATP synthase. We observe dissociation of ATP synthase F1 from FO when we expose primary neurons to glutamate toxicity, suggesting that the non-reversible dissociation of F1 from FO occurs in pathology. We have successfully knocked out five/six alleles of the three genes encoding ATP synthase c-subunit in mouse embryonic stem cells by CRISPR-Cas9, which resulted in 10 percent of the total c-subunit expression. Patch-clamp recordings of mitoplasts isolated from these cells demonstrate low conductance activity that is poorly calcium responsive. These findings confirm that the largest of all inner mitochondrial membrane conductances, and one that forms an uncoupling, non-selective leak channel, resides within the ATP synthase monomer, more specifically within its membrane-embedded c-subunit ring. We are now creating a mouse with a mutant c-subunit that contains a reduced conductance c-subunit. We hypothesize that this mouse will be protected from ischemic heart and brain disease and from degenerative diseases.
  • Role of mitochondria in Fragile X disorder: Loss of function of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) results in unregulated, elevated mRNA translation and aberrant synaptic morphology. We find that mitochondria in neurons of the Fmr1-/y mouse have an inner membrane leak that undermines ATP synthesis and contributes to a replicative phenotype that is a hallmark of immature, dividing cells. We now find that abnormal stoichiometry leading to increased free ATP synthase c-subunit ring contributes to aberrant mRNA translation in Fmr1-/y mouse neurons and human Fragile X Syndrome (FXS) fibroblasts. C-subunit leak inhibition alters metabolism in favor of oxidative phosphorylation, ushering in a new synaptic developmental period, and this critical change fails to occur in Fragile X synapses. The developmental metabolic switch is also dependent on stimulus-induced phosphorylation of translation elongation factor EF2, an event which is lacking in Fmr1-/y synapses and which changes the mRNAs that are translated. We find that FMRP regulates a stimulus-dependent change in mitochondrial metabolism required for synaptic development.
  • Role of Bcl-xL in synaptic plasticity: Long-term potentiation (LTP) and depression (LTD) are the mechanisms that neurons use to modulate their inherent synaptic plasticity and support the storage and recovery of memories in the mammalian brain. The ability to potentiate a synapse over the long term declines significantly in neurodegenerative disorders. In addition to deficiencies in synaptic plasticity, degenerating neurons display acute and chronic mitochondrial dysfunction, suggesting that dysregulated mitochondria play a role in synaptic dysfunction, in addition to their known role in apoptotic cell death. Our previous work has shown that the anti-apoptotic protein Bcl-xL not only prevents somatic cell death, but also potentiates long-term synaptic responses. Here, we show that Bcl-xL is responsible for dramatic changes in ATP levels in hippocampal neurons during LTP. Using fluorescence imaging of a FRET based ATP construct (ATeam) in living hippocampal neurons, we find that LTP induction causes a sharp decrease in ATP levels followed by a persistent long term increase in ATP production. This suggests that after intense synaptic stimulation, neurons may become metabolically more efficient. The long-term increase in ATP levels of LTP-stimulated synapses is blocked by inhibition of Bcl-xL and by inhibition of ATP synthase activity. Bcl-xL inhibition also prevents the long-term increase in surface glutamate receptor insertion. In hippocampal slice recordings, inhibition of Bcl-xL impairs early stage LTP and prevents late stage LTP. Our findings suggest that long term changes in mitochondrial efficiency brought on by activity-dependent translocation of Bcl-xL to mitochondria are required for LTP and shed light upon the role of mitochondrial metabolic programming and dynamics in acute induction and long-term maintenance of learning and memory processing. If such mitochondria-dependent metabolic changes fail to occur, synaptic dysfunction and neurodegeneration may ensue.
  • Role of mitochondrial bioenergetics in Parkinson's Disease: Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the F1FO ATP synthase β subunit to increase the enzymatic activity of the ATP synthase and enhance the efficiency of ATP production. Mutations in DJ-1 or DJ-1 knock out cause loss of mitochondrial inner membrane coupling, resulting in decreased growth of mouse dopaminergic neuronal processes and human fibroblasts. the reason for this is loss of DJ-1 decreases ATP synthase β subunit levels. DJ-1 improves ATP synthase β subunit levels by boosting its translation and by chaperoning β subunit into the mitochondria. We suggest that DJ-1 maximizes inner membrane efficiency by improving F1/FO ratio. This decreases the inner mitochondrial membrane leak, enhancing dopaminergic neuronal process extension.



Coauthors

Research Interests

Endocrinology; Mitochondria; Nervous System; Synaptic Transmission; Neurobiology; Apoptosis

Research Images

c-subunit of the ATP synthase forms the mitochondrial permeability transition pore
Shown are a wild type and mutant c-subunit. The mutant c-subunit has a lower conductance and when expressed in neurons is able to protect the neurons from excitotoxic (glutamate toxicity-induced) cell death.

Selected Publications

  • Dopamine fuels its own release.Chen R, Jonas EA. Dopamine fuels its own release. Nature Neuroscience 2020, 23: 1-2. PMID: 31844312, DOI: 10.1038/s41593-019-0563-4.
  • Inefficient 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 JF, 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. FASEB Journal : Official Publication Of The Federation Of American Societies For Experimental Biology 2020, 34: 7404-7426. PMID: 32307754, PMCID: PMC7692004, DOI: 10.1096/fj.202000283RR.
  • 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.
  • The 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.
  • 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.
  • 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.
  • ATP 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.
  • Parkinson'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.
  • The 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. FASEB Journal : Official Publication Of The Federation Of American Societies For Experimental Biology 2019, 33: 8925-8934. PMID: 31034784, PMCID: PMC6988861, DOI: 10.1096/fj.201802754R.
  • Vitamin E Prevents ΔN-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19).Park HA, 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 PMID: 31224188, PMCID: PMC6574370, DOI: 10.1093/cdn/nzz052.P14-024-19.
  • 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 PMID: 31905614, PMCID: PMC6982044, DOI: 10.3390/ijms21010220.
  • 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 And Differentiation 2018, 25: 542-572. PMID: 29229998, PMCID: PMC5864235, DOI: 10.1038/s41418-017-0020-4.
  • BDNF signaling: Harnessing stress to battle mood disorder.Licznerski P, Jonas EA. BDNF signaling: Harnessing stress to battle mood disorder. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 3742-3744. PMID: 29592951, PMCID: PMC5899500, DOI: 10.1073/pnas.1803645115.
  • Nutritional Regulators of Bcl-xL in the Brain.Park HA, Broman K, Stumpf A, Kazyak S, Jonas EA. Nutritional Regulators of Bcl-xL in the Brain. Molecules (Basel, Switzerland) 2018, 23 PMID: 30463183, PMCID: PMC6278276, DOI: 10.3390/molecules23113019.
  • 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 And Differentiation 2017, 24: 1963-1974. PMID: 28777375, PMCID: PMC5635221, DOI: 10.1038/cdd.2017.123.
  • Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis.Zille M, Karuppagounder SS, Chen Y, Gough PJ, Bertin J, Finger J, Milner TA, Jonas EA, Ratan RR. Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke; A Journal Of Cerebral Circulation 2017, 48: 1033-1043. PMID: 28250197, PMCID: PMC5613764, DOI: 10.1161/STROKEAHA.116.015609.
  • 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 2017, 49: 13-25. PMID: 26868013, PMCID: PMC4981558, DOI: 10.1007/s10863-016-9652-1.
  • Phylogenetic 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.
  • The MIFstep in parthanatos.Jonas E. The MIFstep in parthanatos. Science (New York, N.Y.) 2016, 354: 36-37. PMID: 27846484, DOI: 10.1126/science.aai8756.
  • 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 2015, 87: 1-8. PMID: 25332381, PMCID: PMC4279080, DOI: 10.1124/mol.114.095661.
  • Bcl-xL is necessary for neurite outgrowth in hippocampal neurons.Park HA, Licznerski P, Alavian KN, Shanabrough M, Jonas EA. Bcl-xL is necessary for neurite outgrowth in hippocampal neurons. Antioxidants & Redox Signaling 2015, 22: 93-108. PMID: 24787232, PMCID: PMC4281845, DOI: 10.1089/ars.2013.5570.
  • 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: 10580-5. PMID: 24979777, PMCID: PMC4115574, DOI: 10.1073/pnas.1401591111.
  • 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: 773-85. PMID: 23792689, PMCID: PMC3725990, DOI: 10.1038/ncb2791.
  • 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: 574-80. PMID: 22366758, PMCID: PMC3862259, DOI: 10.1038/nn.3054.
  • Bcl-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: 1224-33. PMID: 21926988, PMCID: PMC3186867, DOI: 10.1038/ncb2330.
  • 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 2008, 99: 1515-22. PMID: 18160428, PMCID: PMC2836590, DOI: 10.1152/jn.00598.2007.
  • 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: 4892-7. PMID: 18347331, PMCID: PMC2290755, DOI: 10.1073/pnas.0800628105.
  • Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons.Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R, McNay EC, Yu T, Schwarzenbacher R, Bossy B, Bossy-Wetzel E, Bennett MV, Pypaert M, Hickman JA, Smith PJ, Hardwick JM, Jonas EA. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2008, 105: 2169-74. PMID: 18250306, PMCID: PMC2542873, DOI: 10.1073/pnas.0711647105.
  • PKC-induced intracellular trafficking of Ca(V)2 precedes its rapid recruitment to the plasma membrane.Zhang Y, Helm JS, Senatore A, Spafford JD, Kaczmarek LK, Jonas EA. PKC-induced intracellular trafficking of Ca(V)2 precedes its rapid recruitment to the plasma membrane. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2008, 28: 2601-12. PMID: 18322103, PMCID: PMC2830008, DOI: 10.1523/JNEUROSCI.4314-07.
  • BCL-xL regulates synaptic plasticity.Jonas E. BCL-xL regulates synaptic plasticity. Molecular Interventions 2006, 6: 208-22. PMID: 16960143, DOI: 10.1124/mi.6.4.7.
  • 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. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2006, 26: 6851-62. PMID: 16793892, PMCID: PMC4758341, DOI: 10.1523/JNEUROSCI.5444-05.2006.
  • Prolonged activation of mitochondrial conductances during synaptic transmission.Jonas EA, Buchanan J, Kaczmarek LK. Prolonged activation of mitochondrial conductances during synaptic transmission. Science (New York, N.Y.) 1999, 286: 1347-50. PMID: 10558987.
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