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...