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Home , Mitochondrion, Neurotransmission

The : the powerhouse behind Professor Elizabeth Jonas neurotransmission ‘We think we have found a key molecule that forms a major death-inducing mitochondrial channel’

THE MITOCHONDRION: THE POWERHOUSE BEHIND NEUROTRANSMISSION

Professor Elizabeth Jonas and her colleagues at Yale University study the function of cell components called Ca2+ Ca2+ Ca2+ mitochondria and their role in neurotransmission. In particular, Professor Jonas is interested in characterising how 3. Calcium is released from mitochondria. 2. Repeated action potentials (tetanus) invade When another invades 1. An1. action An action potential potential invades inv adesthe terminal. the 2. Repeated action potentials 3. Calcium is released from channels in the mitochondrial membrane affect neuronal function during processes like formation and terminal. the terminal, the increased calcium levels Someterminal. vesicles fuse, releasing (tetanus) invade terminal. mitochondria. learning, and how they enhance or reduce neuronal viability during disease. Many vesicles fuse. from mitochondrial release plus plasma .Some vesicles fuse, releasing Many vesicles fuse. When another action potential neurotransmitter. CalciumCalcium is ta isk takenen up up into into mitochondria. invadesmembrane the terminal, Ca2+ influx increase vesicle mitochondria. the fusion,increased potentiating calcium levelsneurotransmission. from mitochondrial release plus plasma membrane Ca2+ influx Neurotransmission – firing on all can have profound effects on neuronal but they participate in carefully regulating increase , cylinders. function and viability, and implications in calcium levels during neurotransmission. and calcium dynamics of neurotransmission the mitochondrial permeability transition potentiatingand its classical neurotr roleansmission. is to prevent other disease. This process also has important effects on and on studying how these interact, like pore. The channel can open and close, members of the Bcl-2 family from initiating form an incredibly complex ATP production by the mitochondria and filling in pieces of a jigsaw puzzle. In fact, allowing mitochondrial contents to travel a program known as . network throughout our bodies, and play The nuts and bolts of neurotransmission: can affect how excitable the is. If Professor Jonas is credited with developing through it. Exposure to high concentrations However, Professor Jonas’ team has a fundamental physiological role. Neurons the mitochondrial system. the calcium-regulating or ATP-producing a completely new technique to study ion of calcium results in permeability transition found that Bcl-xL can also improve the form the link between brain and body by processes become altered this can change channels inside living cells, using two pore opening which may act physiologically efficiency of mitochondrial function during transmitting information to and from the Much of the demands of the excitability of a neuron over time, or can electrodes, whereby one electrode is in the neuron to help re-release sequestered neurotransmission by interacting with the brain and spinal cord to peripheral tissues neurotransmission are met by a small even cause the death of the neuron. In fact, sheathed inside another and is used to calcium, but, if open for a longer time, ATP synthase and the mitochondrial such as our muscles. The brain can encode present in neurons called the channels in mitochondria are important probe for ion channels in the membranes of may also disrupt mitochondrial function. permeability transition pore. Jonas’ team information as patterns of neural impulses mitochondrion. Mitochondria are membrane- factors in cell death and may contribute , like mitochondria. Interestingly, These events ultimately lead to loss of finds that Bcl-xL essentially contributes to that pass from neuron to neuron. Neurons bound structures which produce a substance substantially to the permanent alteration in her initial goal when applying this technique normal neurotransmission and neuronal prevention of leaking of H+ through also comprise the brain and spinal called (ATP), which neuronal function in the brain that underlies was to find ion channels on the membranes death. In addition, the team is interested the mitochondrial permeability transition itself and normal neuronal function forms the is used by the neuron as a source of energy learning and memory formation and other of large secretory granules in in other molecules that can interact with, pore, which improves the ability of the basis for a diverse set of processes including during neurotransmission. Mitochondrial forms of neural plasticity. These processes neurons. She was surprised when instead, and affect the behaviour of mitochondrial mitochondria to increase ATP production, thought, memory formation and movement. efficiency refers to how much ATP is may go very wrong in neurodegenerative she discovered calcium release channels in pores or otherwise modulate mitochondrial while reducing the metabolic demands on Neurotransmission is the procedure by which produced per molecule of or diseases like Alzheimer’s or Parkinson’s mitochondria, a discovery which sparked activity and neurotransmission. The Bcl-2 mitochondria. These processes may partially neuronal cells communicate with each other. taken up by a cell or , and when this disease; therefore, mitochondrial dysfunction her intense interest in mitochondrial family of , originally identified in underlie the potential of Bcl-xL to protect Typically, neurons do not directly touch each process is inefficient less ATP is produced. is heavily implicated in these diseases. channels and the role they play in disease. cancer cells, is involved in the regulation neurons from degeneration and may also other, but rather exchange information at Neurotransmission also involves the uptake Understanding what substances pass in and of mitochondrial membrane permeability play a role in memory formation in the brain. specialised structures surrounding a very of calcium through small channels or How is this process regulated? out of the mitochondrion, when they move among other processes. Several members of thin gap between neurons called a . pores in the neuronal membrane. Calcium in and out, and what molecules permit or the family tend to promote cell death, while At a synapse, an activated neuron, through facilitates the release of Professor Elizabeth Jonas and her team are block their movement and why, are key others prevent cell death. This comprises a which a neural impulse has travelled, will from the neuron. However, once interested in the regulation of ion transport elements of Professor Jonas’ research. For particularly important function for cancer So how do these complex phenomena release molecules called neurotransmitters neurotransmission is complete, the calcium across the mitochondrial membrane, with example, the team discovered that a segment cells, which rely on anti-death Bcl-2 family on a small scale in neurons relate to which can travel across the synaptic cleft and that entered the neuron needs to be cleared, a view to understanding the role of the of an enzyme called ATP synthase, which members to promote their cancer-inducing appreciable effects in human beings? One bind to receptors in a second neuron. In this to allow the system to reset. Mitochondria mitochondrion in normal activities such as is involved in the production of ATP in the behaviour. In neurons the anti-death Bcl-2 mechanism these factors can affect is manner, the neural impulse can propagate play a role in helping to mop up this calcium learning and memory, as well as its role in mitochondrion, functions as a channel in the family members prevent death due to many synaptic plasticity, which is the tendency of a along the second neuron and continue on its through an intricate system of channels in disease processes which result in abnormal inner mitochondrial membrane, where it is forms of injury or aging, and this function synapse to become stronger or weaker over way. As you might have guessed, this process their membranes. They also re-release the neuronal activity or neuronal cell death. embedded. Professor Jonas believes that in in neurons is termed neuroprotection. time, as a result of changes in its activity. requires energy, and alterations in the sequestered calcium and so not only do they The team focuses on identifying the most this discovery, the team has uncovered the One member of the family is called Bcl-xL. It is hypothesised that this process could mechanism by which this energy is provided help to reset calcium levels in the neuron, important molecular players in the energy identity of a very important channel, called Bcl-xL spans the mitochondrial membrane underlie our ability to create and

WWW.SCIENTIAPUBLICATIONS.COM WWW.SCIENTIAPUBLICATIONS.COM PROFESSOR ELIZABETH JONAS Professor Jonas and her team have hypothesised that neuroprotective molecules like Bcl-xL may prevent the onset of neurodegenerative disease through their interactions with mitochondrial ion channels.

While pro-apoptotic Bcl-xL appears to contribute to neuronal cell death processes in diseases like , full length Bcl-xL may promote neuronal survival under non-ischemic conditions. In fact, Professor Jonas and her team have hypothesised that neuroprotective molecules like Bcl-xL may prevent the onset of neurodegenerative processes and consequently neurodegenerative disease. Conversely, the loss of neuroprotective molecules like Bcl-xL, could permit neurodegenerative processes to occur. results in the loss of synaptic function, or in neuronal death, and underlies a host of diseases including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease among others. These conditions are a significant source of mortality and suffering. Consequently, research that could provide retain learned information, in addition to potential involvement in Meet the researcher answers about the molecular basis for neurodegeneration, such as that pathologies like , depression, , Alzheimer’s Disease undertaken by Professor Jonas, could be very valuable to society. Professor Elizabeth Jonas and in movement disorders such as Parkinson’s Disease. Mitochondrial ion channels play a role in synaptic plasticity, through changes in the The next steps for Professor Jonas’ team. Associate Professor uptake or re-release of calcium into the neuron, which can enhance or Dept. of Internal Medicine () and Dept. of suppress neurotransmitter release into the synapse, but also perhaps ‘We now want to find out exactly how Bcl-xL assists the mitochondria to through long lasting changes in the efficiency of energy production over alter their efficiency during formation of memories in the Yale University School of Medicine, New Haven, CT time (mitochondrial plasticity). In these ways, increased levels of Bcl-xL and how Bcl-xL works in other neurons in the brain’ Professor Jonas can enhance the potential of a neuron to release neurotransmitter over tells Scientia. The team is also interested in finding out more about how the long-term. Therefore, changes in the activity of mitochondrial ion this interaction may go awry in neurodegenerative conditions. These channels could potentially play a significant role in brain development results could aid in finding new drug targets to help in the treatment of Professor Elizabeth Jonas is an Associate Professor in the Department KEY COLLABORATORS and in preventing brain aging. such conditions. Future research will look at other proteins that interact of Internal Medicine (Endocrinology) and the Department of with ATP synthase to improve the efficiency of mitochondrial function. Neuroscience at Yale University. After completing a BA at Yale University, J Marie Hardwick, Johns Hopkins University, USA Cell death One example is DJ1. This is highly expressed in the brain and Prof. Jonas completed her M.D. at New York University. Subsequently, Leonard K Kaczmarek, Yale University, USA in cancer cells, and is mutated in a familial form of Parkinson’s disease, she completed residencies in Neurology and Internal Medicine at the R Suzanne Zukin, Albert Einstein College of Medicine, USA In addition to changing levels of neuronal activity, mitochondrial ion suggesting a strong link with the pathogenesis of Parkinson’s disease. Yale University School of Medicine and a Postdoctoral Fellowship Kambiz N Alavian, Imperial College, London, UK channels also control cell death. In diseases such as stroke, the blood in Pharmacology at the same location. She began an Assistant Dimitry Ofengeim, Harvard, USA supply to an area of the brain is cut off by the blockage of a blood In addition to looking at neurodegenerative disease, Professor Professorship in the Department of Internal Medicine at Yale University John Hickman, IMI PREDECT vessel feeding the brain. The neurons in the affected area are deprived Jonas also plans to study the role of mitochondrial efficiency in before becoming an Associate Professor in the Department of Internal Valentin Gribkoff, Yale University, USA of nutrients and oxygen and die, potentially leading to impairments neurodevelopmental disorders. Fragile X syndrome is one such disorder Medicine (Endocrinology) and the Department of Neuroscience at Yale Casey Kinnally, NYU, USA in cognition and mobility, including paralysis. Some of the affected in the category of autism spectrum disease, resulting in intellectual University. Evgeny Pavlov, NYU, USA cells undergo a process called apoptosis, during which a complex disability. Fragile X disorder is caused by an abnormality in the FMR1 George A Porter, University of Rochester, USA biochemical chain of events causes them to be destroyed. This which encodes the FMRP protein. ‘Preliminarily, we have found CONTACT Keith Nehrke, University of Rochester, USA process involves mitochondrial activity and Bcl-2 proteins. that Bcl-xL and FMRP work together to protect neurons and particularly Paul Brooks, University of Rochester, USA Professor Jonas’ team investigated the role of Bcl-xL in neurons which during brain development’ says Professor Jonas. The E: [email protected] had been starved of nutrients and oxygen during the process known as FMRP and Bcl-xL combination may work to regulate the efficiency T: (+1) 203 785 3087 FUNDING neuronal . They discovered that Bcl-xL was a key component of mitochondrial function and this in turn seems to regulate protein W: http://bbs.yale.edu/people/elizabeth_jonas-1.profile of the apoptotic cascade in this type of cell, and that during stroke synthesis efficiency during synaptic plasticity. The team suspects that NIH/NINDS or ischemic brain injury, neurons tended to form a slightly different the abnormal FMRP protein may disrupt mitochondrial function and CURRENT LAB MEMBERS FRAXA Research Foundation form of Bcl-xL, that induced, rather than protected from, apoptosis. thereby prevent the normal regulation of protein synthesis in Fragile X Knopp Inc. Surprisingly, fighting this pro-death form of Bcl-xL was easy. The group patients’ brains. These findings could underlie in part the pathogenesis Nelli Mnatsakanyan GeminX Pharmaceuticals used a drug that was already known to block the anti-apoptotic full of the disorder. Han-A Park American Established Investigator length form of Bcl-xL in cancer cells. In the Jonas team hands, the drug, Pawel Licznerski Grass Faculty Award ABT-737, also appeared to effectively interact with the pro-death form The implications of the results of this neurological research are Paige Miranda American Foundation for Aging Research of Bcl-xL, significantly reducing the amount of cell death caused by applicable to a variety of diverse disease states. The team with Rongmin Chen Hartford Foundation Fellowship the brain ischemia. The team concluded that Bcl-xL might represent Dr Kambiz Alavian at Imperial College, London, have also recently Jing Wu Hellman Fellowship an important drug target in the treatment of diseases like stroke. If a started to determine the role of the ATP synthase channel they Frank R. Lillie Fellowship drug could inhibit the pro-apoptotic form of Bcl-xL in stroke patients, have identified as the mitochondrial permeability transition pore, Ann E. Kammer Memorial Fellowship Fund then perhaps levels of cell death and functional impairment could be in the growth of cancer. In other studies at Yale, they have begun to National Science Foundation POWRE Program/NSF 97-91 dramatically reduced. characterise the structure of the channel in detail using a technique AASH/Glaxo Wellcome Headache Research Award called cryo- microscopy, in order to better understand how it and Endocrine Research Council Award functions.

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