The mitochondrion: the powerhouse behind Professor Elizabeth Jonas neurotransmission ‘We think we have found a key molecule that forms a major cell death-inducing mitochondrial ion 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 action potential 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 memory 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 neurotransmitter.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 vesicle fusion, 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 Neurons 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 cell death program known as apoptosis. network throughout our bodies, and play The nuts and bolts of neurotransmission: can affect how excitable the neuron 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 energy 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 enzyme and the mitochondrial such as our muscles. The brain can encode organelle 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 organelles, 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+ ions through also comprise the brain and spinal tissue called adenosine triphosphate (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 invertebrate 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 glucose or oxygen 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 organism, and when this disease; therefore, mitochondrial dysfunction her intense interest in mitochondrial family of proteins, 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 synapse. pores in the neuronal membrane. Calcium in and out, and what molecules permit or the family tend to promote cell death, while Synaptic plasticity At a synapse, an activated neuron, through facilitates the release of neurotransmitters 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 memories 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 stroke, full length Bcl-xL may promote neuronal survival under non-ischemic conditions. In fact, Professor Jonas