Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 516, Issue 2, Pages 160-172Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2011.10.012
Keywords
Membrane-bound glutathione transferase; Mitochondrial permeability transition; Thiol cross-linking; Peroxynitrite; Adenine nucleotide translocator; Cyclophilin D
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We have previously shown that the mitochondrial membrane-bound glutathione transferase (mtMGST1) is activated via thiol modifications and contributes to the mitochondrial permeability transition (MPT) pore. In the present study we aimed to confirm the role of mtMGST1 in the oxidant peroxynitrite (PON)-induced MPT pore opening. PON induced the swelling of mitoplasts (inner membranes including the matrix) as well as of the mitochondria. The swelling was markedly suppressed by ADP [an adenine nucleotide translocator (ANT) ligand] and partially suppressed by cyclosporin A or by GST inhibitors (tannic acid, S-hexylglutathione). Dithiothreitol (DTT), a disulfide bond-reducing reagent, prevented the swelling. Western blot analyses of mitoplast proteins after PON-induced swelling positively identified the high molecular weight protein (HMP) including mtMGST1 (monomer), ANT (48 kDa), and cyclophilin D (CypD, 30 kDa). The HMP level was decreased according to suppression of the swelling and undetectable after DTT treatment. The HMP formation and swelling were also suppressed by a Ca(2+) chelating agent and antioxidants. These results suggest that the HMP is a disulfide-linked protein complex involving mtMGST1, ANT, CypD and function as a MPT pore in PON-induced swelling, in which the Ca(2+) released by PON might play an important role in the complex formation. (C) 2011 Elsevier Inc. All rights reserved.
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