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Ca 2+ ‐dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP‐ribose) polymerase‐1 activation during glutamate excitotoxicity
Author(s) -
Duan Yuntao,
Gross Robert A.,
Sheu SheyShing
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.145409
Subject(s) - excitotoxicity , reactive oxygen species , mitochondrion , mitochondrial ros , oligomycin , glutamate receptor , microbiology and biotechnology , biology , poly adp ribose polymerase , uniporter , biochemistry , chemistry , cytosol , receptor , polymerase , enzyme , atpase
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.