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Duan Y, Gross RA, Sheu SS: Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly (ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol. 2007 Dec 15;585(Pt 3):741-58. Epub 2007 Oct 18.
Mitochondrial Ca (2+) uptake and poly (ADP-ribose) polymerase-1 (PARP-1) activation are both required for glutamate-induced excitotoxic neuronal death. Since activation of the glutamate receptors can induce increased levels of reactive oxygen species (ROS), we investigated the relationship of mitochondrial Ca (2+) uptake and ROS generation, and the possibility that ROS increase is a required signal for PARP-1 activation in cultured striatal neurons. Based on the spatial profile of NMDA-induced ROS generation, we found that only mitochondria showed a significant ROS increase within 30 min after NMDA receptor activation. This ROS increase was inhibited by the mitochondrial complex inhibitors rotenone and oligomycin, but not by the cytosolic phospholipase A (2) or xanthine oxidase inhibitors. Mitochondrial ROS generation was also inhibited by both removal of Ca (2+) from extracellular medium and blockage of mitochondrial Ca (2+) uptake by either a mitochondrial uncoupler or a Ca (2+) uniporter inhibitor. Furthermore, both DNA damage and PARP-1 activation induced by NMDA treatment was inhibited by blocking mitochondrial Ca (2+) uptake or by antioxidants. Our results demonstrate that ROS production during the early stage of acute excitotoxicity derives primarily from mitochondria and is Ca (2+)-dependent. More importantly, the increase of mitochondrial ROS serves as a signal for PARP-1 activation, suggesting that concomitant mitochondrial Ca (2+) uptake and PARP-1 activation constitute a unified mechanism for excitotoxic neuronal death. |
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