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The Journal of Neuroscience, August 1, 2000, 20(15):5715-5723

Delayed Mitochondrial Dysfunction in Excitotoxic Neuron Death: Cytochrome c Release and a Secondary Increase in Superoxide Production

C. Marc Luetjens¹, Nguyen Truc Bui¹, Bernd Sengpiel³, Gudrun Münstermann¹, Monika Poppe¹, Aaron J. Krohn¹, Elke Bauerbach³, Josef Krieglstein³, and Jochen H. M. Prehn^{1, 2, 3}

¹ Interdisciplinary Center for Clinical Research, Research Group "Apoptosis and Cell Death" and ² Department of Pharmacology and Toxicology, Westphalian Wilhelms-University, D-48149 Münster, and ³ Department of Pharmacology and Toxicology, Philipps-University, D-35032 Marburg, Germany

An increased production of superoxide has been shown to mediate glutamate-induced neuron death. We monitored intracellular superoxide production of hippocampal neurons during and after exposure to the glutamate receptor agonist NMDA (300 µM). During a 30 min NMDA exposure, intracellular superoxide production increased significantly and remained elevated for several hours after wash-out of NMDA. After a 5 min exposure, superoxide production remained elevated for 10 min, but then rapidly returned to baseline. Mitochondrial membrane potential also recovered after wash-out of NMDA. However, recovery of mitochondria was transient and followed by delayed mitochondrial depolarization, loss of cytochrome c, and a secondary rise in superoxide production 4-8 hr after NMDA exposure. Treatment with a superoxide dismutase mimetic before the secondary rise conferred the same protection against cell death as a treatment before the first. The secondary rise could be inhibited by the complex I inhibitor rotenone (in combination with oligomycin) and mimicked by the complex III inhibitor antimycin A. To investigate the relationship between cytochrome c release and superoxide production, human D283 medulloblastoma cells deficient in mitochondrial respiration ( cells) were exposed to the apoptosis-inducing agent staurosporine. Treatment with staurosporine induced mitochondrial release of cytochrome c, caspase activation, and cell death in control and cells. However, a delayed increase in superoxide production was only observed in control cells. Our data suggest that the delayed superoxide production in excitotoxicity and apoptosis occurs secondary to a defect in mitochondrial electron transport and that mitochondrial cytochrome c release occurs upstream of this defect.

Key words: excitotoxicity; glutamate; NMDA; mitochondria; reactive oxygen species; superoxide; cytochrome c; respiratory chain; apoptosis

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20155715-09$05.00/0

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