Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death

Viacheslav Li, Tatiana Brustovetsky, Nickolay Brustovetsky

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 μM glutamate, but not to 100 μM glutamate. Ca2+ influx into Ppif-/- neurons was not diminished in comparison with WT neurons judging by 45Ca accumulation. In both types of neurons, 100 μM glutamate produced greater Ca2+ influx than 10 μM 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.

Original languageEnglish (US)
Pages (from-to)171-182
Number of pages12
JournalExperimental Neurology
Volume218
Issue number2
DOIs
StatePublished - Aug 1 2009

Fingerprint

Glutamic Acid
Permeability
Calcium
Neurons
cyclophilin D
Knockout Mice
Cell Death
Wounds and Injuries
Proteins

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death. / Li, Viacheslav; Brustovetsky, Tatiana; Brustovetsky, Nickolay.

In: Experimental Neurology, Vol. 218, No. 2, 01.08.2009, p. 171-182.

Research output: Contribution to journalArticle

@article{be3dca02f4314a6282d14d7d28dace36,
title = "Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death",
abstract = "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 μM glutamate, but not to 100 μM glutamate. Ca2+ influx into Ppif-/- neurons was not diminished in comparison with WT neurons judging by 45Ca accumulation. In both types of neurons, 100 μM glutamate produced greater Ca2+ influx than 10 μM 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.",
author = "Viacheslav Li and Tatiana Brustovetsky and Nickolay Brustovetsky",
year = "2009",
month = "8",
day = "1",
doi = "10.1016/j.expneurol.2009.02.007",
language = "English (US)",
volume = "218",
pages = "171--182",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death

AU - Li, Viacheslav

AU - Brustovetsky, Tatiana

AU - Brustovetsky, Nickolay

PY - 2009/8/1

Y1 - 2009/8/1

N2 - 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 μM glutamate, but not to 100 μM glutamate. Ca2+ influx into Ppif-/- neurons was not diminished in comparison with WT neurons judging by 45Ca accumulation. In both types of neurons, 100 μM glutamate produced greater Ca2+ influx than 10 μM 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.

AB - 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 μM glutamate, but not to 100 μM glutamate. Ca2+ influx into Ppif-/- neurons was not diminished in comparison with WT neurons judging by 45Ca accumulation. In both types of neurons, 100 μM glutamate produced greater Ca2+ influx than 10 μM 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.

UR - http://www.scopus.com/inward/record.url?scp=67649785237&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649785237&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2009.02.007

DO - 10.1016/j.expneurol.2009.02.007

M3 - Article

C2 - 19236863

AN - SCOPUS:67649785237

VL - 218

SP - 171

EP - 182

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 2

ER -