The Metabolic Hypothesis Revisited

The resurgence of suggestions that point to the mitochondria as having a key role in oxygen sensing in the genetic and molecular basis of hypoxic chemosensitivity (Burke and Kwast, 1999, Hand, 1999) indicates that this is a good time to reconsider the concept of the mitochondrial basis for oxygen sensing in the carotid body (CB). The mitochondrion is the primary site for oxygen metabolism and thus is the largest consumer of oxygen in the cell. Therefore, it is a logical site for sensing cellular changes in oxygen (Zhu and Bunn, 1999). Also, the flux of electrons through the respiratory chain and cytochrome c oxidase is effected by oxygen concentration in yeast and mammalian cells. In addition, the for oxygen binding to the cytochrome c oxidase is effected by oxygen concentration (Kwast et al., 1999). Thus, the respiratory chain in the mitochondria would certainly be a suitable candidate for housing the oxygen sensor. In this regard, carbon monoxide (CO) is a powerful tool for studying the involvement of cytochrome oxidase in oxygen sensing. It is a molecule that is a structural analog of oxygen and binds to the oxygen binding site of cytochrome oxidase (Wilson et al., 1994). It freely and quickly diffuses into the cell. Its binding affinity for cytochrome oxidase is less than that of and the bound CO is photodissociable (Warburg, 1949; Lahiri et al., 1993). This property makes it possible to obtain a photochemical action spectrum by determining changes in neural discharge (ND) of the carotid sinus nerve (CSN) from the isolated, perfused-superfused CB (Wilson et al., 1994)) in the presence of CO plus with light pluses of varying wavelength. For our