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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 585/3/741    most recent jphysiol.2007.145409v2 jphysiol.2007.145409v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Duan, Y. Articles by Sheu, S.-S. Search for Related Content PubMed PubMed Citation Articles by Duan, Y. Articles by Sheu, S.-S. Related Collections Neuroscience

¹ Department of Pharmacology and Physiology
² Mitochondrial Research and Innovation Group
³ Department of Neurology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA

Mitochondrial Ca²⁺ 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 Ca²⁺ 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 A₂ or xanthine oxidase inhibitors. Mitochondrial ROS generation was also inhibited by both removal of Ca²⁺ from extracellular medium and blockage of mitochondrial Ca²⁺ uptake by either a mitochondrial uncoupler or a Ca²⁺ uniporter inhibitor. Furthermore, both DNA damage and PARP-1 activation induced by NMDA treatment was inhibited by blocking mitochondrial Ca²⁺ uptake or by antioxidants. Our results demonstrate that ROS production during the early stage of acute excitotoxicity derives primarily from mitochondria and is Ca²⁺-dependent. More importantly, the increase of mitochondrial ROS serves as a signal for PARP-1 activation, suggesting that concomitant mitochondrial Ca²⁺ uptake and PARP-1 activation constitute a unified mechanism for excitotoxic neuronal death.

(Received 21 September 2007; accepted after revision 15 October 2007; first published online 18 October 2007)
Corresponding author S.-S. Sheu: University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA. Email: sheyshing_sheu{at}urmc.rochester.edu

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