When oxygen is scarce, mitochondria pump out reactive oxygen species (ROS) that alert the cell to the shortage, say Bell et al. (page 1029).
Mitochondria are needed to activate hypoxia-responsive pathways, which help restore O2 levels and are jumpstarted by the stabilization of hypoxia-inducible factor (HIF)-1α. But mitochondria do many things—they consume O2, churn out ATP, and produce ROS. So just how cells sense hypoxia is hotly debated.
By uncoupling mitochondrial O2 consumption from ROS production, Bell et al. now prove that the ROS are the key. Using genetic manipulations—particularly tricky in mitochondrial studies, which often rely instead on chemical inhibitors—the group created cells that have a loss of cytochrome b activity. These cells could not respire or make ATP, but they did still produce ROS and respond to hypoxia by stabilizing HIF-1α.
The additional loss of ROS production blocked HIF-1α stabilization. Although ROS are formed at mitochondrial complexes I, II, and III, only those leaking from III seemed to be essential for hypoxia signaling, according to RNAi and inhibitor studies. The authors would now like to track down the machinery within complex III that senses the low O2 and then dials up ROS formation.
HIF-1α is stabilized when it is no longer hydroxylated by prolyl hydroxylase enzymes (PHDs), but it is currently unclear how ROS block these enzymes. As PHDs require O2 for their action, they were once thought to be the main hypoxia sensor. But even extremely low O2 levels are enough for hydroxylation. The ROS pathway instead gives cells a chance to start building new O2-supplying blood vessels before conditions become so severe.