GLUTAMATE-INDUCED NEURON DEATH REQUIRES MITOCHONDRIAL CALCIUM-UPTAKE

We have investigated the role of mitochondrial calcium buffering in ex citotoxic cell death. Glutamate acts at NMDA receptors in cultured rat forebrain neurons to increase the intracellular free calcium concentr ation. Although concurrent inhibition of mitochondrial calcium uptake substantially enhanced this cytoplasmic calcium increase, it significa ntly reduced glutamate-stimulated neuronal cell death. Mitochondrial i nhibition did not affect nitric oxide production or MAP kinase phospho rylation, which have been proposed to mediate excitotoxicity. These re sults indicate that very high levels of cytoplasmic calcium are not ne cessarily toxic to forebrain neurons, and that potential-driven uptake of calcium into mitochondria is required to trigger NMDA-receptor-sti mulated neuronal death.