The Keith Peters Building
Mitochondria and acute oxygen sensing by arterial chemoreceptors
Oxygen (O2) is essential for life, particularly in mammals, due to its role as an electron acceptor in oxidative phosphorylation. An O2 deficit (hypoxia), even if transient, can produce severe pathological consequences in sensitive tissues such as the brain or heart. Changes in O2 tension (PO2) alter the activity of O2-sensitive ion channels in tissues of the homeostatic acute O2-sensing system, thereby leading to compensatory responses. The best-studied arterial chemoreceptors are the carotid body (CB) glomus cells, which contain O2-sensitive K+ channels in the plasma membrane. Inhibition of these channels during hypoxia leads to cell depolarization, Ca2+ influx through voltage-gated channels, and exocytotic transmitter release, which activates sensory fibers terminating in the brainstem. This chain of events induces hyperventilation and sympathetic activation in a time scale of seconds. Although this membrane model of acute O2 sensing is widely accepted, the mechanisms underlying detection of O2 levels by ion channels have remained elusive. The responsiveness of glomus cells to hypoxia is prevented by rotenone, a blocker of mitochondrial complex I (MCI), which competes with the binding of ubiquinone. Genetically-modified mice lacking the Ndufs2 gene, which encodes an MCI protein essential for ubiquinone binding, show a lack of ventilatory response to hypoxia and a loss of sensitivity of glomus cells to decreases in PO2. Gene expression profile analyses have shown that O2-sensing glomus cells in the CB express specific ion channels, metabolic enzymes and mitochondrial subunits. Cellular experiments suggest that hypoxia induces a slow-down of the electron transport chain in these cells, resulting in an increased QH2/Q ratio. This, in turns, induces NADH accumulation and the production of reactive oxygen species that inhibit the activity of K+ channels. These data suggest a mitochondria-to-membrane signaling mechanism, which provides a comprehensive model that explains acute O2 sensing.