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

Changes in O-2 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 O-2 inhibits apoptosis caused by NGF deprivation. Low O-2 exposure blocked cytochrome c release after NGF withdrawal, in part by suppressing the up-regulation of BIMEL. Forced BIMEL expression removed the block to cytochrome c release but did not prevent protection by low O-2. Exposing neurons to low O-2 also activated hypoxia-inducible factor (HIF) and expression of a stabilized form of HIF-1 alpha (HIF-1 alpha(PP -> AG)) inhibited cell death in normoxic, NGF-deprived cells. Targeted deletion of HIF-1a partially suppressed the protective effect of low 02, whereas deletion of HIF-1 alpha combined with forced BIMEL expression completely reversed the ability of low O-2 to inhibit cell death. These data suggest a new model for how O-2 tension can influence apoptotic events that underlie trophic factor deprivation-induced cell death.