Glutathione S-transferase π localizes in mitochondria and protects against oxidative stress |
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Authors: | Shinji Goto Miho Kawakatsu Shin-ichi Izumi Yoshishige Urata Kan Kageyama Yoshito Ihara Takehiko Koji Takahito Kondo |
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Institution: | 2. Professor and Chairman, Department of Cell and Molecular Pharmacology, John C. West Chair of Cancer Research, Medical University of South Carolina, Charleston, South Carolina, USA;3. Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA |
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Abstract: | Glutathione S-transferases (GSTs) are multifunctional enzymes involved in the protection of cellular components against anti-cancer drugs or peroxidative stress. Previously we found that GST π, an isoform of the GSTs, is transported into the nucleus. In the present study, we found that GST π is present in mitochondria as well as in the cytosol and nucleus in mammalian cell lines. A construct comprising the 84 amino acid residues in the amino-terminal region of GST π and green fluorescent protein was detected in the mitochondria. The mutation of arginine to alanine at positions 12, 14, 19, 71, and 75 in full-length GST π completely abrogated the ability to distribute in the mitochondria, suggesting that arginine, a positively charged residue, is required for the mitochondrial transport of GST π. Chemicals generating reactive oxygen species, such as rotenone and antimycin A, decreased cell viability and reduced mitochondrial membrane potential. The overexpression of GST π diminished these changes. GST π-targeting siRNA abolished the protective effect of GST π on the mitochondria under oxidative stress. The findings indicate that the peptide signal is conducive to the mitochondrial localization of GST π under steady-state conditions without alternative splicing or posttranslational modifications such as proteolysis, suggesting that GST π protects mitochondria against oxidative stress. |
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