Mechanisms underlying regulating expression of mitochondrial gene to determine death and survival in neurons

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A decline in the mitochondrial RNA transcripts and protein synthesis, as well as mitochondrial DNA damage, is considered to induce mitochondrial injury to cause neuronal death. To evaluate involvement of mitochondrial dysfunction in glutamate-induced neuronal death, in this study, we examined the effects of glutamate exposure on mitochondrial RNA level in primary cultured cortical neurons of mice. Cerebral cortex was dissected in 15 days-old fetal mouse to obtain neural cells. Cultured cortical neurons (12 DIV) obtained were exposed to glutamate for 15 min at 100 μM. Glutamate treatment led to a significant decrease in mRNA of ND1 and ND6, which are subunits of NADH-ubiquinone oxidoreductase, before cell death. As mitochondrial RNAs level is regulated at least in part by RNA degradation by RNase-L, we next examined the effect of glutamate exposure on expression of RNase-L. RT-PCR analysis revealed that glutamate was effective in increasing the level of RNase-L mRNA at least 2-12 h after treatment. The increase in expression of RNase-L was abolished by the NMDA receptor antagonist MK801. There results suggest that activation of NMDA receptor by glutamate reduces mitochondrial RNA level through enhanced expression of RNase-L in primary cultured cortical neurons.