Proposed model of oxygen sensing and signaling. In oxygenated cells, a flavo-heme protein functions as an NADPH oxidase, transferring electrons through the flavin (FAD) and heme to molecular oxygen, generating superoxide (O₂⁻), which, in the presence of iron, is converted to hydroxyl radical (OH·) and other reactive oxygen species (ROS). As a result, HIF-1 is oxidatively modified so that it is recognized by the proteasome and rapidly degraded. Cobalt (Co²⁺) as well as other transition metals (Ni²⁺ and Mn²⁺) may block the iron-dependent degradation of HIF-1. At low oxygen tension, as well as in the presence of an iron chelator or one of the above-mentioned transition metals, HIF-1 is stable and can form a heterodimer with constitutively expressed HIF-1β, thereby activating HIF-1, which translocates to the nucleus and binds to response elements in hypoxia inducible genes.