The cellular basis for diverse responses to oxygen

Mammalian cells have divergent responses to varying oxygen levels. Cells exposed to low oxygen levels (hypoxia) activate the transcription factor hypoxia-inducible factor-1 (HIF-1) as an adaptive response. Cells exposed to hypoxia do not undergo senescence or cell death and do not diminish ATP levels. By contrast, cells exposed to high oxygen levels (hyperoxia) undergo senescence and cell death and decrease their ATP levels, yet do not activate HIF-1. Despite these divergent responses with respect to senescence, cell death, metabolism, and gene expression, the signaling events in both systems are mediated by the generation of mitochondrial-derived reactive oxygen species (ROS). This perspective reviews the role of signaling through mitochondrial ROS in hypoxic and hyperoxic environments.