抄録
We previously observed, under a video-enhanced contrast-differential interference contrast (VEC-DIC) microscope, that glutamate induces mitochondrial dysfunction and nuclear granulation within 20 min in neurons. The granulation corresponds to DNA fragmentation following the increase in nucleoplasmic Ca2+ concentration ([Ca2+]n). In the present study, to determine the role of mitochondria in developing nuclear granulation, we examined, in cultured hippocampal neurons, the morphological changes and the increase in [Ca2+]n associated with nuclear changes following an application of carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP). The morphological changes were observed with a VEC-DIC microscope, and [Ca2+]n assessed with fluo-3 under a confocal laser microscope. We observed that: 1) FCCP (10 μM) induced the nuclear changes identical to those induced by glutamate; 2) FCCP persistently increased [Ca2+]n before inducing the nuclear changes; 3) the removal of extracellular Ca2+ did not affect these processes; and 4) following FCCP exposure inositol trisphosphate (IP3) concentration in the neuron increased, which was detected with green fluorescent protein that translocates from the plasma membrane to the cytoplasm when IP3 increases. We conclude that mitochondrial dysfunction stimulates the IP3 pathway, increased [Ca2+]n, and induced rapid DNA fragmentation, which aggravates the process of glutamate excitotoxicity. [Jpn J Physiol 54 Suppl:S249 (2004)]
