Mitochondria and neuronal glutamate excitotoxicity.
The role of mitochondria in the control of glutamate excitotoxicity is investigated. The response of cultured cerebellar granule cells to continuous glutamate exposure is characterised by a transient elevation in cytoplasmic free calcium concentration followed by decay to a plateau as NMDA receptors partially inactivate. After a variable latent period, a secondary, irreversible increase in calcium occurs (delayed calcium deregulation, DCD) which precedes and predicts subsequent cell death. DCD is not controlled by mitochondrial ATP synthesis since it is unchanged in the presence of the ATP synthase inhibitor oligomycin in cells with active glycolysis. However, mitochondrial depolarisation (and hence inhibition of mitochondrial calcium accumulation) without parallel ATP depletion (oligomycin plus either rotenone or antimycin A) strongly protects the cells against DCD. Glutamate exposure is associated with an increase in the generation of superoxide anion by the cells, but superoxide generation in the absence of mitochondrial calcium accumulation is not neurotoxic. While it is concluded that mitochondrial calcium accumulation plays a critical role in the induction of DCD we can find no evidence for the involvement of the mitochondrial permeability transition.
Neurosciences Institute, Department of Pharmacology and Neuroscience, University of Dundee, Dundee DD1 9SY, UK. d.g.nicholls@dundee.ac.uk
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000648:ultrastructure; D004734:Energy Metabolism; D018698:Glutamic Acid / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D009498:Neurotoxins; D013481:Superoxides; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D002118:Calcium