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Glutathione Transport Regulates FasL‐induced Apoptosis in Lymphoma Cells by Modulating Apoptotic Volume Decrease and Changes in Ionic Homeostasis

Intracellular glutathione (GSH) depletion is an important hallmark observed in apoptosis. We have previously reported that GSH depletion by its extrusion regulates apoptosis independent of ROS and oxidative stress. However, the mechanisms by which GSH depletion regulates apoptosis are still unclear. We sought to study the relationship between GSH transport and changes in ionic homeostasis associated with cell shrinkage or apoptotic volume decrease (AVD) during FasL‐induced apoptosis in Jurkat cells. The reduction in GSHi in response to FasL was shown to occur in two stages paralleled by distinct degrees of AVD. Inhibition of GSH efflux prevented AVD, [K+]i loss, and the activation of distinct ionic conductances including Kv1.3 and ORCC (outward rectifying Cl‐ channel). Reciprocally, stimulation of GSHi loss by MK571 accelerated the loss of [K+]i, AVD and consequently the progression of the execution phase of apoptosis. Interestingly, GSH depletion was largely unaffected by prevention of [K+]i loss using high extracellular K+ medium. However, high extracellular K+ inhibited the acceleration of the execution phase of apoptosis and its stimulation by MK571. These results suggest that GSH depletion regulates AVD and changes in intracellular ionic homeostasis during FasL‐induced apoptosis, and that the regulation of apoptosis by GSH depletion is mediated, at least in part, by the regulation of K+ loss.