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

Exp Neurol. 2009 Aug;218(2):171-82. doi: 10.1016/j.expneurol.2009.02.007. Epub 2009 Feb 21.

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 microM glutamate, but not to 100 microM glutamate. Ca(2+) influx into Ppif(-/-) neurons was not diminished in comparison with WT neurons judging by (45)Ca accumulation. In both types of neurons, 100 microM glutamate produced greater Ca(2+) influx than 10 microM glutamate. We hypothesize that greater Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Cell Culture Techniques
  • Cell Death
  • Cell Membrane Permeability / drug effects*
  • Cerebral Cortex / cytology
  • Cyclophilin D
  • Cyclophilins / genetics*
  • Cyclophilins / metabolism*
  • Dose-Response Relationship, Drug
  • Genotype
  • Glutamic Acid / pharmacology*
  • Hydrogen-Ion Concentration / drug effects
  • Immunohistochemistry
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Polymerase Chain Reaction

Substances

  • Cyclophilin D
  • Luminescent Proteins
  • PPIF protein, mouse
  • Glutamic Acid
  • Cyclophilins
  • Calcium