AbstractNeuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)‐differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of survival following H2O2‐induced oxidative stress or NGF deprivation was preceded by a decrease in mitochondrial membrane potential (ΔΨm), increase in reactive oxygen species (ROS), and up‐regulation of cyclin D1 and phosphorylation (Ser‐780) of protein retinoblastoma (P‐pRb), without an increase of proliferation rates. Treatment with H2O2, but not NGF deprivation, also induced the phosporylation (Ser‐10) of p27kip1 and the appearance of a cleaved P‐p27kip1 fragment of about 15 kDa. The extent of cell cycle activation appeared to be inversely correlated to the duration of toxic stimuli (pulse/continuous). H2O2‐induced mitogenic responses appeared to be mediated by induction of P‐MAPK and P‐Akt and were blocked by p38MAPK and JNK inhibitors as well as by the CDK inhibitor flavopiridol (Flav) and by sodium selenite (Sel), a component of selenoproteins, including glutathione peroxidases. Inhibition of p38MAPK and JNK, instead, did not affect cyclin D1 changes following NGF deprivation. Finally, both Flav hydrochloride and Sel partially prevented mitochondrial dysfunction and cell death following NGF withdrawal or H2O2 toxicity, but not during oxidative stress in the absence of NGF. Taken together, these data suggest that H2O2‐induced oxidative stress can determine distinct patterns of mitogenic responses as a function of mitochondrial dysfunction depending on 1) intensity/duration of stress stimuli and/or 2) presence of NGF. © 2011 Wiley‐Liss, Inc.