Peroxovanadate inhibits Ca2+ release from mitochondria |
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Authors: | Salvi M Toninello A Schweizer M Friess S D Richter C |
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Institution: | (1) Department of Biological Chemistry, University of Padova and CNR Center for the Study of Biomembranes, 35121 Padova (Italy), IT;(2) Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), 8092 Zurich (Switzerland), Fax + 41 1 632 11 21, e-mail: richter@bc.biol.ethz.ch, CH;(3) Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH), 8093 Zurich (Switzerland), CH |
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Abstract: | Mitochondria contain a specific Ca2+ release pathway which operates when oxidized mitochondrial pyridine nucleotides are hydrolyzed. NAD+ hydrolysis and therefore Ca2+ release is possible when some vicinal thiols are cross-linked. Here we report that the thiol oxidant peroxovanadate inhibits
the specific Ca2+ release pathway. In mitochondria, peroxovanadate causes a complete loss of reduced glutathione, which is not accompanied
by formation of glutathione disulfide, and a partial loss of protein thiols. In model reactions, peroxovanadate oxidizes reduced
glutathione predominantly to the sulfonate derivative, but does not react with glutathione disulfide. When the vicinal thiols
relevant for Ca2+ release are cross-linked, Ca2+ release is no longer inhibited by peroxovanadate. Conversely, pretreatment of mitochondria with peroxovanadate makes them
insensitive to compounds promoting the disulfide state. These results suggest that peroxovanadate inhibits the prooxidant-induced
Ca2+ release from mitochondria by (i) depleting mitochondria of reduced glutathione and (ii) oxidizing the vicinal thiols relevant
for Ca2+ release to a state higher than disulfide, presumably the sulfonate state. The findings provide further insight into the regulation
of Ca2+ release from intact mitochondria, and may be relevant for a better understanding of the action of peroxovanadate in cells,
where the compound can be insulin mimetic.
Received 28 March 2002; received after revision 8 May 2002; accepted 15 May 2002 |
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Keywords: | : Vicinal thiol intactness glutathione peroxynitrite gliotoxin disulfide glutathione oxidation sulfonate |
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