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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

Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Albacete, Spain (M.G.-L., M.F.G, R.M.M.-F.M., F.J.F.-G., J.J.); Department of Physiology and RCSI Neuroscience Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland (C.G.C., J.H.M.P.); Cell Signaling and Apoptosis Group, Departament de Ciències Mèdiques Bàsiques, University of Lleida and Hospital Arnau de Vilanova, Lleida, Spain (M.F.S., J.X.C.); and Centro Regional de Investigaciones Biomedicas, Albacete, Spain (M.G.-L., M.F.G., R.M.M.-F.M., F.J.F.-G., J.J.)

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.

Received for publication September 8, 2006.

Accepted for publication December 15, 2006.

Address correspondence to: Joaquin Jordán, Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02006, Albacete, Spain. E-mail: joaquin.jordan{at}uclm.es

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