Prolonged, but not acute, glutathione depletion promotes Fas-mediated mitochondrial permeability transition and apoptosis in mice

Glutathione depletion either decreased or increased death-receptor-mediated apoptosis in previous studies. Comparison of the durations of glutathione depletion before death-receptor stimulation in these studies might suggest a different effect of prolonged versus acute thiol depletion. We compared t he effects of the prolonged glutathione depletion caused by a sulfur amino acid-deficient (SAA(-)) diet and the acute depletion caused by a single dos e of phorone on hepatic apoptosis triggered by the administration of an ago nistic anti-Fas antibody. The chronic SAA(-) diet did not affect hepatic Fa s or Bcl-XL, but increased p53 and Bar, and exacerbated Fas-mediated mitoch ondrial membrane depolarization, electron-microscopy-proven outer mitochond rial membrane rupture, cytochrome c translocation to the cytosol, and caspa se 3 activation. These effects were prevented by cyclosporin A, an inhibito r of mitochondrial permeability transition. The SAA(-) diet increased inter nucleosomal DNA fragmentation, the percentage of apoptotic hepatocytes, ser um alanine transaminase (ALT) activity, and mortality after Fas stimulation . Despite a similar decrease in hepatic glutathione, administration of a si ngle dose of phorone 1 hour before the anti-Fas antibody did not change p53 or Bar, and did not enhance Fas-induced mitochondrial permeability transit ion and toxicity. However, 4 repeated doses of phorone (causing more prolon ged glutathione depletion) increased Bar and Fas-mediated toxicity. In conc lusion, a chronic SAA(-) diet, but not acute phorone administration, increa ses p53 and Bar, and enhances Fas-induced mitochondrial permeability transi tion and apoptosis. Thiol depletion could cause oxidative stress that requi res several hours to increase p53; the latter induces Bar, which translocat es to mitochondria after Fas stimulation.