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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 regulating the production or release of ATP, by buffering and re-releasing calcium during vesicle fusion and recycling, and by contributing to the regulation of their own fate via autophagic engulfment (mitophagy). BCL-2 family proteins, by their actions at mitochondrial membranes, normally play an important role in cell death at the soma, but can also strengthen or weaken synaptic connections through their interaction with mitochondria. Mitochondria also influence the actions of other organelles, in particular the endoplasmic reticulum and this interaction regulates intracellular calcium and protein synthesis.

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 eventually, after the loss of many synaptic connections, whether a neuron will survive or undergo untimely death.

Specialized Terms: Mitochondrial ion channel; Regulation of apoptosis; Control of the strength of synaptic transmission in the nervous system; permeability transition pore.

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). We have now purified ATP synthase from porcine heart mitochondria and performed single-channel studies. 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 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 from E. coli plasma membranes. C-subunit purified using this technique forms large conductance channels identical to those purified from HEK-293 cells. The 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 observed dissociation of ATP synthase F1 from FO when we expose primary hippocampal 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 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 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.
  • 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. Previous work in cardiomyocytes showed that developmental maturation is dependent on closure of a mitochondrial membrane leak. We now find that mild depletion of ATP synthase c-subunit or inhibition of the c-subunit leak with ATP synthase interacting agents decreases mRNA translation in Fmr1-/y mouse neurons and human Fragile X Syndrome (FXS) fibroblasts. Leak inhibition alters metabolism in favor of oxidative phosphorylation. We argue that the developmental metabolic switch is dependent on stimulus-induced phosphorylation of translation elongation factor EF2, an event which is lacking in Fmr1-/y synapses. We suggest that FMRP regulates a stimulus-dependent change in mitochondrial metabolism required for synaptic development.


Research Interests

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

Research Images

Selected Publications