Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death
Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death
复制标题
DOI：
10.1016/j.expneurol.2009.02.007
复制
发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Brustovetsky, Nickolay
中科院分区：
文献类型：
--
作者：
Li, Viacheslav;Brustovetsky, Tatiana;Brustovetsky, Nickolay
In the present study we tested the hypothesis that the cyclophilin D-dependent (CyD) mitochondrial permeability transition (CyD-mPT) plays an important role in glutamate-triggered delayed calcium deregulation (DCD) and excitotoxic neuronal death. We used Cultured cortical neurons from wild-type C57BL/6 and cyclophilin D-knockout mice (Ppif(-/-)). Induction of the mPT was identified by following the rapid secondary acidification of mitochondrial matrices monitored with mitochondrially targeted pH-sensitive yellow fluorescent protein. Suppression of the CyD-mPT due to genetic CyD ablation deferred DCD and mitochondrial depolarization, and increased the survival rate after exposure of neurons to 10 mu m glutamate, but not to 100 mu M glutamate. Ca2+ influx into Ppif(-/-) neurons was not diminished in comparison with WT neurons judging by Ca-45 accumulation. In both types of neurons, 100 mu M glutamate produced greater Ca2+ influx than 10 mu M glutamate. We hypothesize that greater Ca2+ influx produced by higher glutamate rapidly triggered the CyD-independent mPT in both WT and Ppif(-/-) neurons equalizing their responses to supra-physiologic excitotoxic insults. In neurons exposed to moderate but pathophysiologically-relevant glutamate concentrations, an induction of the CyD-mPT appears to play an important role in mitochondrial injury contributing to DCD and cell death. (C) 2009 Elsevier Inc. All rights reserved.
