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Reactive oxygen species and p38 mitogen-activated protein kinase activate Bax to induce mitochondrial cytochrome c release and apoptosis in response to malonate.

Authors
  • Gomez-Lazaro, M1
  • Galindo, M F
  • Melero-Fernandez de Mera, R M
  • Fernandez-Gómez, F J
  • Concannon, C G
  • Segura, M F
  • Comella, J X
  • Prehn, J H M
  • Jordan, J
  • 1 Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02006, Albacete, Spain.
Type
Published Article
Journal
Molecular pharmacology
Publication Date
March 2007
Volume
71
Issue
3
Pages
736–743
Identifiers
PMID: 17172466
Source
Medline
License
Unknown

Abstract

Malonate, an inhibitor of mitochondrial complex II, is a widely used toxin to study neurodegeneration in Huntington's disease and ischemic stroke. We have shown previously that malonate increased reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells, leading to oxidative stress, cytochrome c release, and apoptotic cell death. Expression of a green fluorescent protein-Bax fusion protein in SH-SY5Y neuroblastoma cells demonstrated a Bax redistribution from the cytosol to mitochondria after 12 to 24 h of malonate treatment that coincided with mitochondrial potential collapse and chromatin condensation. Inhibition of Bax translocation using furosemide, as well as Bax gene deletion, afforded significant protection against malonate-induced apoptosis. Further experiments revealed that malonate induced a prominent increase in the level of activated p38 mitogen-activated protein (MAP) kinase and that treatment with the p38 MAP kinase inhibitor SKF86002 potently blocked malonate-induced Bax translocation and apoptosis. Treatment with vitamin E diminished ROS production, reduced the activation status of p38 MAP kinase, inhibited Bax translocation, and protected against malonate-induced apoptosis. Our data suggest that malonate-induced ROS production and subsequent p38 MAP kinase activation mediates the activation of the pro-apoptotic Bax protein to induce mitochondrial membrane permeabilization and neuronal apoptosis.

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