Different fates of intracellular glutathione determine different modalities of apoptotic nuclear vesiculation

U937 monocytic cells show two main apoptotic nuclear morphologies, budding and cleavage, that are the result of two independent morphological routes, since they never interconvert one into the other, and are differently modulated by stressing or physiological apoptogenic agents [Exp Cell Res 1996; 223:340–347]. With the aim of understanding which biochemical alterations are at the basis of these alternative apoptotic morphologies, we performed an in situ analysis that showed that in U937 cells intracellular glutathione (GSH) is lost in cells undergoing apoptosis by cleavage, whereas it is maintained in apoptotic budding cells. Lymphoma cells BL41 lose GSH in apoptosis, and show the cleavage nuclear morphology; the same cells latently infected with Epstein Barr Virus (E2r line) undergo apoptosis without GSH depletion and show the budding nuclear morphology. GSH depletion is not only concomitant to, but is the determinant of the cleavage route, since the inhibition of apoptotic GSH efflux with cystathionine or methionine shifts the apoptotic morphology from cleavage to budding. Accordingly, cystathionine or methionine antagonizes apoptosis in the all-cleavage BL41, without affecting the all-budding E2r.