Reactive Oxygen Species and p38 Mitogen-Activated Protein Kinase Activate Bax to Induce Mitochondrial Cytochrome c Release and Apoptosis in Response to Malonate
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...
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Veröffentlicht in: | Molecular pharmacology 2007-03, Vol.71 (3), p.736-743 |
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Zusammenfassung: | 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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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.106.030718 |