Acute oxygen sensing is essential for humans under hypoxic environments or pathologic conditions. This is achieved by the carotid body (CB), the key arterial chemoreceptor, along with other peripheral chemoreceptor organs, such as the adrenal medulla (AM). Although it is widely accepted that inhibition of K+ channels in the plasma membrane of CB cells during acute hypoxia results in the activation of cardiorespiratory reflexes, the molecular mechanisms by which the hypoxic signal is detected to modulate ion channel activity are not fully understood. Using conditional knockout mice lacking mitochondrial complex I (MCI) subunit NDUFS2, we have found that MCI generates reactive oxygen species and pyridine nucleotides, which signal K+ channels during acute hypoxia. Comparing the transcriptomes from CB and AM, which are O2-sensitive, with superior cervical ganglion, which is practically O2-insensitive, we have found that CB and AM contain unique metabolic gene expression profiles. The "signature metabolic profile" and their biophysical characteristics could be essential for acute O2 sensing by chemoreceptor cells.