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A more recent version of this article appeared on February 11, 2005
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M410661200v1
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Papers In Press, published online ahead of print November 23, 2004
J. Biol. Chem, 10.1074/jbc.M410661200
Submitted on September 16, 2004
Revised on November 10, 2004
Accepted on November 23, 2004

Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse

Elizabeth A. Jonas, John A. Hickman, J. Marie Hardwick, and Leonard K. Kaczmarek

Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT 06520

Corresponding Author: elizabeth.jonas{at}yale.edu

One of the earliest effects of hypoxia on neuronal function is to produce a rundown of synaptic transmission, and more prolonged hypoxia results in neuronal death. An increase in the permeability of the outer mitochondrial membrane, controlled by BCL-2 family proteins, occurs in response to stimuli that trigger cell death. By patch clamping mitochondrial membranes inside the presynaptic terminal of a squid giant synapse, we have now found that several minutes of hypoxia trigger the opening of large multi-conductance channels. The channel activity is induced concurrently with the attenuation of synaptic responses that occurs under hypoxic conditions. Hypoxia-induced channels are inhibited by NADH, an agent that inhibits large conductance channels produced by a pro-apoptotic fragment of BCL-xL in these synaptic mitochondria. The appearance of hypoxia-induced channels was also prevented by the caspase/cysteine protease inhibitor zVAD, which inhibits proteolysis of BCL-xL during hypoxia. Both NADH and zVAD reduced significantly the rate of decline of synaptic responses during hypoxia. Our results indicate that an increase in outer mitochondrial channel activity is a very early event in the response of neurons to hypoxia, and suggest that this increase in activity may contribute to the decline in synaptic function during hypoxia.


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