Professor Elizabeth Jonas and her colleagues at Yale University study the function of cell components called mitochondria and their role in neurotransmission. In particular, Professor Jonas is interested in characterising how channels in the mitochondrial membrane affect neuronal function during processes like memory formation and learning, and how they enhance or reduce neuronal viability during disease.
Neurotransmission – firing on all
Neurons form an incredibly complex
network throughout our bodies, and play
a fundamental physiological role. Neurons
form the link between brain and body by
transmitting information to and from the
brain and spinal cord to peripheral tissues
such as our muscles. The brain can encode
information as patterns of neural impulses
that pass from neuron to neuron. Neurons
also comprise the brain and spinal tissue
itself and normal neuronal function forms the
basis for a diverse set of processes including
thought, memory formation and movement.
Neurotransmission is the procedure by which
neuronal cells communicate with each other.
Typically, neurons do not directly touch each
other, but rather exchange information at
specialised structures surrounding a very
thin gap between neurons called a synapse.
At a synapse, an activated neuron, through
which a neural impulse has travelled, will
release molecules called neurotransmitters
which can travel across the synaptic cleft and
bind to receptors in a second neuron. In this
manner, the neural impulse can propagate
along the second neuron and continue on its
way. As you might have guessed, this process
requires energy, and alterations in the
mechanism by which this energy is provided
can have profound effects on neuronal
function and viability, and implications in
The nuts and bolts of neurotransmission: the mitochondrial system. Much of the energy demands of neurotransmission are met by a small organelle present in neurons called the mitochondrion. Mitochondria are membranebound structures which produce a substance called adenosine triphosphate (ATP), which is used by the neuron as a source of energy during neurotransmission. Mitochondrial efficiency refers to how much ATP is produced per molecule of glucose or oxygen taken up by a cell or organism, and when this process is inefficient less ATP is produced. Neurotransmission also involves the uptake of calcium through small channels or pores in the neuronal membrane. Calcium facilitates the release of neurotransmitters from the neuron. However, once neurotransmission is complete, the calcium that entered the neuron needs to be cleared, to allow the system to reset. Mitochondria play a role in helping to mop up this calcium through an intricate system of channels in their membranes. They also re-release the sequestered calcium and so not only do they help to reset calcium levels in the neuron, but they participate in carefully regulating calcium levels during neurotransmission. This process also has important effects on ATP production by the mitochondria and can affect how excitable the neuron is. If the calcium-regulating or ATP-producing processes become altered this can change the excitability of a neuron over time, or can even cause the death of the neuron. In fact, channels in mitochondria are important factors in cell death and may contribute substantially to the permanent alteration in neuronal function in the brain that underlies learning and memory formation and other forms of neural plasticity. These processes may go very wrong in neurodegenerative diseases like Alzheimer’s or Parkinson’s disease; therefore, mitochondrial dysfunction is heavily implicated in these diseases.
‘We think we have found a key molecule that forms a major cell death-inducing mitochondrial ion channel’
How is this process regulated?
Professor Elizabeth Jonas and her team are
interested in the regulation of ion transport
across the mitochondrial membrane, with
a view to understanding the role of the
mitochondrion in normal activities such as
learning and memory, as well as its role in
disease processes which result in abnormal
neuronal activity or neuronal cell death.
The team focuses on identifying the most
important molecular players in the energy
and calcium dynamics of neurotransmission
and on studying how these interact, like
filling in pieces of a jigsaw puzzle. In fact,
Professor Jonas is credited with developing
a completely new technique to study ion
channels inside living cells, using two
electrodes, whereby one electrode is
sheathed inside another and is used to
probe for ion channels in the membranes of
organelles, like mitochondria. Interestingly,
her initial goal when applying this technique
was to find ion channels on the membranes
of large secretory granules in invertebrate
neurons. She was surprised when instead,
she discovered calcium release channels in
mitochondria, a discovery which sparked
her intense interest in mitochondrial
channels and the role they play in disease.
Understanding what substances pass in and
out of the mitochondrion, when they move
in and out, and what molecules permit or
block their movement and why, are key
elements of Professor Jonas’ research. For
example, the team discovered that a segment
of an enzyme called ATP synthase, which
is involved in the production of ATP in the
mitochondrion, functions as a channel in the
inner mitochondrial membrane, where it is
embedded. Professor Jonas believes that in
this discovery, the team has uncovered the
identity of a very important channel, called
the mitochondrial permeability transition
pore. The channel can open and close,
allowing mitochondrial contents to travel
through it. Exposure to high concentrations
of calcium results in permeability transition
pore opening which may act physiologically
in the neuron to help re-release sequestered
calcium, but, if open for a longer time,
may also disrupt mitochondrial function.
These events ultimately lead to loss of
normal neurotransmission and neuronal
death. In addition, the team is interested
in other molecules that can interact with,
and affect the behaviour of mitochondrial
pores or otherwise modulate mitochondrial
activity and neurotransmission. The Bcl-2
family of proteins, originally identified in
cancer cells, is involved in the regulation
of mitochondrial membrane permeability
among other processes. Several members of
the family tend to promote cell death, while
others prevent cell death. This comprises a
particularly important function for cancer
cells, which rely on anti-death Bcl-2 family
members to promote their cancer-inducing
behaviour. In neurons the anti-death Bcl-2
family members prevent death due to many
forms of injury or aging, and this function
in neurons is termed neuroprotection.
One member of the family is called Bcl-xL.
Bcl-xL spans the mitochondrial membrane and its classical role is to prevent other
members of the Bcl-2 family from initiating
a cell death program known as apoptosis.
However, Professor Jonas’ team has
found that Bcl-xL can also improve the
efficiency of mitochondrial function during
neurotransmission by interacting with the
ATP synthase enzyme and the mitochondrial
permeability transition pore. Jonas’ team
finds that Bcl-xL essentially contributes to
prevention of leaking of H+ ions through
the mitochondrial permeability transition
pore, which improves the ability of the
mitochondria to increase ATP production,
while reducing the metabolic demands on
mitochondria. These processes may partially
underlie the potential of Bcl-xL to protect
neurons from degeneration and may also
play a role in memory formation in the brain.
Synaptic plasticity So how do these complex phenomena on a small scale in neurons relate to appreciable effects in human beings? One mechanism these factors can affect is synaptic plasticity, which is the tendency of a synapse to become stronger or weaker over time, as a result of changes in its activity. It is hypothesised that this process could underlie our ability to create memories and retain learned information, in addition to potential involvement in pathologies like addiction, depression, autism, Alzheimer’s Disease and in movement disorders such as Parkinson’s Disease. Mitochondrial ion channels play a role in synaptic plasticity, through changes in the uptake or re-release of calcium into the neuron, which can enhance or suppress neurotransmitter release into the synapse, but also perhaps through long lasting changes in the efficiency of energy production over time (mitochondrial plasticity). In these ways, increased levels of Bcl-xL can enhance the potential of a neuron to release neurotransmitter over the long-term. Therefore, changes in the activity of mitochondrial ion channels could potentially play a significant role in brain development and in preventing brain aging.
Cell death In addition to changing levels of neuronal activity, mitochondrial ion channels also control cell death. In diseases such as stroke, the blood supply to an area of the brain is cut off by the blockage of a blood vessel feeding the brain. The neurons in the affected area are deprived of nutrients and oxygen and die, potentially leading to impairments in cognition and mobility, including paralysis. Some of the affected cells undergo a process called apoptosis, during which a complex biochemical chain of events causes them to be destroyed. This process involves mitochondrial ion channel activity and Bcl-2 proteins. Professor Jonas’ team investigated the role of Bcl-xL in neurons which had been starved of nutrients and oxygen during the process known as neuronal ischemia. They discovered that Bcl-xL was a key component of the apoptotic cascade in this type of cell, and that during stroke or ischemic brain injury, neurons tended to form a slightly different form of Bcl-xL, that induced, rather than protected from, apoptosis. Surprisingly, fighting this pro-death form of Bcl-xL was easy. The group used a drug that was already known to block the anti-apoptotic full length form of Bcl-xL in cancer cells. In the Jonas team hands, the drug, ABT-737, also appeared to effectively interact with the pro-death form of Bcl-xL, significantly reducing the amount of cell death caused by the brain ischemia. The team concluded that Bcl-xL might represent an important drug target in the treatment of diseases like stroke. If a drug could inhibit the pro-apoptotic form of Bcl-xL in stroke patients, then perhaps levels of cell death and functional impairment could be dramatically reduced 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 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. Neurodegeneration 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 answers about the molecular basis for neurodegeneration, such as that undertaken by Professor Jonas, could be very valuable to society.
The next steps for Professor Jonas’ team. ‘We now want to find out exactly how Bcl-xL assists the mitochondria to alter their efficiency during formation of memories in the hippocampus and how Bcl-xL works in other neurons in the brain’ Professor Jonas tells Scientia. The team is also interested in finding out more about how this interaction may go awry in neurodegenerative conditions. These results could aid in finding new drug targets to help in the treatment of such conditions. Future research will look at other proteins that interact with ATP synthase to improve the efficiency of mitochondrial function. One example is DJ1. This protein is highly expressed in the brain and in cancer cells, and is mutated in a familial form of Parkinson’s disease, suggesting a strong link with the pathogenesis of Parkinson’s disease. In addition to looking at neurodegenerative disease, Professor Jonas also plans to study the role of mitochondrial efficiency in neurodevelopmental disorders. Fragile X syndrome is one such disorder in the category of autism spectrum disease, resulting in intellectual disability. Fragile X disorder is caused by an abnormality in the FMR1 gene which encodes the FMRP protein. ‘Preliminarily, we have found that Bcl-xL and FMRP work together to protect neurons and particularly synapses during brain development’ says Professor Jonas. The FMRP and Bcl-xL combination may work to regulate the efficiency of mitochondrial function and this in turn seems to regulate protein synthesis efficiency during synaptic plasticity. The team suspects that the abnormal FMRP protein may disrupt mitochondrial function and thereby prevent the normal regulation of protein synthesis in Fragile X patients’ brains. These findings could underlie in part the pathogenesis of the disorder. The implications of the results of this neurological research are applicable to a variety of diverse disease states. The team with Dr Kambiz Alavian at Imperial College, London, have also recently started to determine the role of the ATP synthase channel they have identified as the mitochondrial permeability transition pore, in the growth of cancer. In other studies at Yale, they have begun to characterise the structure of the channel in detail using a technique called cryo-electron microscopy, in order to better understand how it functions.
Meet the researcher
Professor Elizabeth Jonas
Associate Professor Dept. of Internal Medicine (Endocrinology) and Dept. of Neuroscience Yale University School of Medicine, New Haven, CT
Professor Elizabeth Jonas is an Associate Professor in the Department of Internal Medicine (Endocrinology) and the Department of Neuroscience at Yale University. After completing a BA at Yale University, Prof. Jonas completed her M.D. at New York University. Subsequently, she completed residencies in Neurology and Internal Medicine at the Yale University School of Medicine and a Postdoctoral Fellowship in Pharmacology at the same location. She began an Assistant Professorship in the Department of Internal Medicine at Yale University before becoming an Associate Professor in the Department of Internal Medicine (Endocrinology) and the Department of Neuroscience at Yale University.
E: firstname.lastname@example.org T: (+1) 203 785 3087 W: http://bbs.yale.edu/people/elizabeth_jonas-1.profile
CURRENT LAB MEMBERS
Nelli Mnatsakanyan Han-A Park Pawel Licznerski Paige Miranda Rongmin Chen Jing Wu
J Marie Hardwick, Johns Hopkins University, USA Leonard K Kaczmarek, Yale University, USA R Suzanne Zukin, Albert Einstein College of Medicine, USA Kambiz N Alavian, Imperial College, London, UK Dimitry Ofengeim, Harvard, USA John Hickman, IMI PREDECT Valentin Gribkoff, Yale University, USA Casey Kinnally, NYU, USA Evgeny Pavlov, NYU, USA George A Porter, University of Rochester, USA Keith Nehrke, University of Rochester, USA Paul Brooks, University of Rochester, USA
NIH/NINDS FRAXA Research Foundation Knopp Neurosciences Inc. GeminX Pharmaceuticals American Heart Established Investigator Grass Faculty Award American Foundation for Aging Research Hartford Foundation Fellowship Hellman Fellowship Frank R. Lillie Fellowship Ann E. Kammer Memorial Fellowship Fund National Science Foundation POWRE Program/NSF 97-91 AASH/Glaxo Wellcome Headache Research Award Diabetes and Endocrine Research Council Award