Importance of glucose-6-phosphate dehydrogenase activity in cell death

The intracellular redox potential plays an important role in cell survival. The principal intracellular reductant NADPH is mainly produced by the pent ose phosphate pathway by glucose-6-phosphate dehydrogenase (G6PDH), the rat e-limiting enzyme, and by 6-phosphogluconate dehydrogenase. Considering the importance of NADPH, we hypothesized that G6PDH plays a critical role in c ell death. Our results show that 1) G6PDH inhibitors potentiated H2O2-induc ed cell death; 2) overexpression of G6PDH increased resistance to H2O2-indu ced cell death; 3) serum deprivation, a stimulator of cell death, was assoc iated with decreased G6PDH activity and resulted in elevated reactive oxyge n species (ROS); 4) additions of substrates for G6PDH to serum-deprived cel ls almost completely abrogated the serum deprivation-induced rise in ROS; 5 ) consequences of G6PDH inhibition included a significant increase in apopt osis, loss of protein thiols, and degradation of G6PDH; and 6) G6PDH inhibi tion caused changes in mitogen-activated protein kinase phosphorylation tha t were similar to the changes seen with H2O2. We conclude that G6PDH plays a critical role in cell death by affecting the redox potential.