Mitochondrial ion channels in hypoxic neurons
Principal Investigator: Elizabeth Ann Jonas
Abstract: Stroke is a major cause of morbidity and mortality in the United States and presents challenges in the development of disease prevention strategies. Deprivation of nutrients and oxygen supply to brain cells produces immediate death in the most severely affected cells and delayed cell death in some cells that are placed at risk at the first onset of ischemia. The latter form of neuronal death is orchestrated by BCL-2 family proteins, which also regulate cell death during nervous system development. BCL-2 family proteins are present in mitochondrial membranes and become activated to form large conductance ion channel activity in response to many death stimuli, including a low concentration of cellular oxygen. The relationship of the channel activity to the onset of cell death is as yet poorly understood. We have developed patch clamp techniques to record mitochondrial ion channel activity within living neurons and to study the ion channel activity of BCL-2 family proteins in mitochondria isolated from brain. In comparing the channel activity of recombinant BCL-2 family proteins to endogenous activity, we find that the recombinant N-truncated form of BCL-xL, (?N BCL-xL) that is produced by acute proteolytic processing of full length BCL-xL in response to death stimuli, has biophysical and pharmacological similarities to an endogenous mitochondrial channel that appears during transient global ischemia in mammalian brain. The onset of channel activity of ?N BCL-xL may initiate a series of molecular events that leads to selective, delayed cell death in vulnerable CA1 neurons of the hippocampus. We hypothesize that inhibition of the ?N BCL-xL channel activity with the specific inhibitor of BCL-xL, ABT-737, will block cell death in these sensitive neurons after ischemia. Furthermore, if proteolytic processing of full length BCL-xL is necessary for cell death, then hippocampal neurons of a mouse that lacks a cleavable form of BCL-xL may fail to form ?N BCL-xL and fail to die after ischemic insult. These studies will test the hypothesis that ?N BCL-xL is the key regulator of cell death in hippocampal neurons. In addition, these studies will attempt to elucidate the molecular mechanisms underlying cell death in neurons after ischemic brain injury with an eye to developing strategies to combat stroke. PUBLIC HEALTH RELEVANCE: Stroke is a major cause of morbidity and mortality in the United States. We have found that mitochondrial ion channel activity of the pro- and anti-death BCL-2 protein family contributes to the physiological and pathological function of neurons. We hypothesize that in the setting of brain ischemia, such channel activity leads to cell death in the brain and that this death can be prevented by a pharmacological inhibitor of BCL-2-induced mitochondrial ion channels.
Funding Period: 2003-04-01 - 2014-02-28
more information: NIH RePORT
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J Neurosci 26:6851-62. 2006....
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W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
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Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA
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Department of Internal Medicine, Yale University, New Haven, Connecticut 06520, USA
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Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
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W Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
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Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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- Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmissionJohn A Hickman
Institut de Recherches Servier, Croissy sur Seine, France
J Neurophysiol 99:1515-22. 2008..These observations support the possibility that endogenous proteolysis or a functionally equivalent modification of BCL-xL is responsible for the deleterious effects of hypoxia on synaptic activity...
- Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticityElizabeth A Jonas
Dept of Internal Medicine, P O Box 208001, Yale University School of Medicine, New Haven, CT 06520, USA Dept of Neurobiology, P O Box 208020, Yale University School of Medicine, New Haven, CT 06520, USA Electronic address
Biochim Biophys Acta 1842:1168-78. 2014..Bcl-xL is crucial to the normal health of neurons and synapses and its malfunction may contribute to neurodegenerative disease...
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