Details

Autor(en) / Beteiligte

• Gomez-Lazaro, M.
• 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.

Titel

Reactive Oxygen Species and p38 Mitogen-Activated Protein Kinase Activate Bax to Induce Mitochondrial Cytochrome c Release and Apoptosis in Response to Malonate

Ist Teil von

• Molecular pharmacology, 2007-03, Vol.71 (3), p.736-743

Ort / Verlag

United States: American Society for Pharmacology and Experimental Therapeutics

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.