Gliotoxin stimulates Ca2+ release from intact rat liver mitochondria.
Gliotoxin is an epidithiodioxopiperazine compound which can both react with sulfhydryl groups and form hydrogen peroxide. Rat liver mitochondria contain a prooxidant-regulated specific Ca2+ release pathway. Here we report that gliotoxin at low concentrations stimulates Ca2+ release via this pathway in isolated mitochondria. Ca2+ release is not promoted by gliotoxin exposed to disulfide-reducing reagents prior to addition to mitochondria or when its disulfide moiety is dimethylated. Gliotoxin is equally effective in glutathione-depleted and glutathione-adequate mitochondria. This and the unchanged mitochondrial oxygen consumption in the presence of gliotoxin suggest that the compound stimulates Ca2+ release by reacting with critical mitochondrial thiol compounds and not by increasing hydrogen peroxide formation in mitochondria. The gliotoxin-induced Ca2+ release is paralleled by hydrolysis of mitochondrial pyridine nucleotides, and both pyridine nucleotide hydrolysis and Ca2+ release are inhibited by cyclosporin A. These findings provide further insight into the regulation of Ca2+ release from intact mitochondria.
Schweizer
M
M
Laboratory of Biochemistry I, Swiss Federal Institute of Technology (ETH), Zürich.
Richter
C
C
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005912:Gliotoxin / Q000494:pharmacology*; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D013053:Spectrophotometry
D011725:Pyridines; D005912:Gliotoxin; D002118:Calcium