TY - JOUR T1 - Reactive Oxygen Species and p38 Mitogen-Activated Protein Kinase Activate Bax to Induce Mitochondrial Cytochrome <em>c</em> Release and Apoptosis in Response to Malonate JF - Molecular Pharmacology JO - Mol Pharmacol SP - 736 LP - 743 DO - 10.1124/mol.106.030718 VL - 71 IS - 3 AU - M. Gomez-Lazaro AU - M. F. Galindo AU - R. M. Melero-Fernandez de Mera AU - F. J. Fernandez-Gómez AU - C. G. Concannon AU - M. F. Segura AU - J. X. Comella AU - J. H. M. Prehn AU - J. Jordan Y1 - 2007/03/01 UR - http://molpharm.aspetjournals.org/content/71/3/736.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -