The role of mitochondrial dysfunction in the process of glutamate neurotoxicity

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Excitotoxicity related mitochondrial dysfunction has been implicated in the pathogenesis of several neurological disorders including neurodegenerative diseases, stroke, trauma, and seizures. In our laboratory, a video enhanced contrast-differential interference contrast (VEC-DIC) microscope revealed that glutamate induces a rapid change in the neurons. We have also observed that glutamate impairs mitochondrial electron transport. In this study, to understand the role of mitochondrial dysfunction in the glutamate neurotoxicity, we examined : 1) whether mitochondrial respiratory inhibitors could induce the morphological changes ; and 2) how mitochondrial inhibitors would affect the intracellular CaィイD12+ィエD1 concentration, in the rat hippocampal neurons. We compared the results with those induced by glutamate.3-nitropropionic acid (3-NP, 5-10 mM), rotenone (200μM), and FCCP (1-10μM), dose-dependently produced granulation in the nucleus within 20 min that was identical to the findings induced by glutamate showing the early process of DNA fragmentation. Though the nontoxic mitochondrial inhibitors impaired mitochondrial membrane potential, it did not cause rapid nuclear changes. The toxic mitochondrial inhibitors and glutamate markedly increased intranuclear CaィイD12+ィエD1 concentration before they induced nuclear changes. The removal of CaィイD12+ィエD1 in the recording medium did not afffect morphological changes induced by mitochondrial inhibitors, while the treatment prolonged the process of morphological change following glutamate exposure.In conclusion, glutamate impairs mitochondrial membrane potential and increases intranuclear CaィイD12+ィエD1 concentration, and then induces rapid nuclear changes in the hippocampal neurons. During the process, mitochondrial dysfunction can exacerbate increase in intranuclear CaィイD12+ィエD1, and the process of nuclear changes.