Inhibition of NGF deprivation–induced death by low oxygen involves suppression of BIM_EL and activation of HIF-1

Changes in O₂ tension can significantly impact cell survival, yet the mechanisms underlying these effects are not well understood. Here, we report that maintaining sympathetic neurons under low O₂ inhibits apoptosis caused by NGF deprivation. Low O₂ exposure blocked cytochrome c release after NGF withdrawal, in part by suppressing the up-regulation of BIM_EL. Forced BIM_EL expression removed the block to cytochrome c release but did not prevent protection by low O₂. Exposing neurons to low O₂ also activated hypoxia-inducible factor (HIF) and expression of a stabilized form of HIF-1α (HIF-1α^PP→AG) inhibited cell death in normoxic, NGF-deprived cells. Targeted deletion of HIF-1α partially suppressed the protective effect of low O₂, whereas deletion of HIF-1α combined with forced BIM_EL expression completely reversed the ability of low O₂ to inhibit cell death. These data suggest a new model for how O₂ tension can influence apoptotic events that underlie trophic factor deprivation–induced cell death.