Received for publication September 8, 2006.
Revised November 7, 2006.
Accepted for publication December 15, 2006.

REACTIVE OXYGEN SPECIES AND P38 MAPK ACTIVATE BAX TO INDUCE MITOCHONDRIAL CYTOCHROME C RELEASE AND APOPTOSIS IN RESPONSE TO MALONATE

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 previously shown 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 - 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 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 permeabilisation and neuronal apoptosis.

Key words: P38 MAP Kinase, Fluorescence techniques, Regulation - post-transcriptional, Apoptosis, Oxidative stress/antioxidants

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