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Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity
Author(s) -
Nicholls David G.,
JohnsonCadwell Linda,
Vesce Sabino,
Jekabsons Mika,
Yadava Nagendra
Publication year - 2007
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21290
Subject(s) - excitotoxicity , glutamate receptor , bioenergetics , mitochondrion , neuroprotection , nmda receptor , reactive oxygen species , microbiology and biotechnology , calcium , biology , neuron , oxidative phosphorylation , receptor , neuroscience , chemistry , biochemistry , organic chemistry
The pathologic activation of NMDA receptors by glutamate is a major contributor to neuronal cell death after stroke. Receptor activation causes a massive influx of calcium into the neuron that is accumulated by the mitochondria. The favored hypothesis is that the calcium loaded mitochondria generate reactive oxygen species that damage and ultimately killed the neuron. In this review this hypothesis is critically re‐examined with an emphasis on the role played by deficits in ATP generation. Novel techniques are developed to monitor the bioenergetic status of in situ mitochondria in cultured neurons. Applying these techniques to a model of glutamate excitotoxicity suggests that enhanced reactive oxygen species are a consequence rather than a cause of failed cytoplasmic calcium homeostasis (delayed calcium deregulation, [DCD]), but that prior oxidative damage facilitates DCD by damaging mitochondrial ATP generation. This impacts on current hypotheses relating to the neuroprotective effects of mild mitochondrial uncoupling. © 2007 Wiley‐Liss, Inc.