Title

 

Authors

L. Cerioni, M.Fiorani, C. Azzolini and O. Cantoni.
 
Dept. of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61029 Urbino, Italy. 

 

Abstract

We report that a moderate decline of reduced glutathione (GSH) levels causes remarkable changes in Bad sub-cellular distribution. An about 30% reduction of the GSH pool, regardless of whether mediated by diamide or DL-Buthionine-[S,R]-sulfoximine, indeed promoted loss of the fraction of Bad normally associated with mitochondria of untreated U937 cells. Under the same conditions, there was evidence of phosphorylation of Akt at serine 473, selectively blunted by wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Interestingly, inhibition of these events was followed by an unexpected lethal response, preceded by early translocation of Bax to the mitochondrial compartment, prevented by inhibitors of mitochondrial permeability transition and characterised by morphological and biochemical features of apoptosis.  Collectively, the results herein presented demonstrate that mild redox imbalance associated with slight reduction of the GSH pool commits U937 cells to apoptosis, however prevented by events leading to PI3K/Akt-dependent mitochondrial loss of Bad.