FIG. 12.

Schematic representation of the results. H₂O₂ triggers two parallel and independent pathways, one leading to induction of autophagy, the other to transient Akt phosphorylation. Induction of autophagy depends on the mitochondrial generation of hydroxyl radicals, which arise from Fenton reaction between H₂O₂ and redox-active iron. The mTOR pathway is inactive in oxidative-stressed cells. Akt phosphorylation does not preclude autophagy but prevents apoptosis in H₂O₂-stressed cells. However, prolonged incubation in the presence of H₂O₂ leads to Akt dephosphorylation and autophagy-dependent cell death. DFO, by sequestering iron within lysosomes, prevents the prompt formation of hydroxyl radicals (as well as of superoxide anion, which appears later) and, consequently, of autophagy and apoptosis induced by H₂O₂. DFO also prevents Akt dephosphorylation. 3MA and siRNA-beclin-1 prevents autophagy and cell death.