Carotid body O2 chemoreception and mitochondrial oxidative phosphorylation

Abstract

The effect on carotid chemoreceptor afferents of oligomycin, an inhibitor of mitochondrial oxidative phosphorylation that does not affect energy conservation, was studied in 20 cats that were anesthetized, paralyzed, and artificially ventilated. Responses of single or a few chemoreceptor afferents to changes in arterial O2 tension (PaO2) at constant arterial CO2 tension were recorded. In addition, responses to nicotine, cyanide, and antimycin A or carbonyl cyanide p-tri-fluoromethoxyphenylhydrazone (FCCP) were tested in normoxia. Oligomycin (50-500 microgram) was administered by close intra-arterial injection, and the same tests were repeated at timed intervals. Initially, oligomycin caused vigorous stimulation of carotid chemoreceptor activity. Subsequently, although the afferent fibers were still active and could be vigorously stimulated by nicotine, they no longer responded to changes in PaO2 or to doses of cyanide, antimycin A, or FCCP. These results separate stimulation of chemoreceptor afferents by hypoxia and metabolic inhibitors and uncouplers from that by nicotine and suggest that intact oxidative phosphorylation, required for maintenance of the intracellular high-energy phosphate levels, forms the basis of O2 chemoreception in the carotid body.

Oxygen sensing in yeast: Evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes

“…What all of these treatments have in common is blockage of electron transport through cytochrome c oxidase. Cytochrome c oxidase also has been implicated as a probable oxygen sensor and in the regulation of hypoxic genes in a number of mammalian cells, including carotid body cells (12)(13)(14)49), hepatocytes (17,18,50), and cardiomyocytes (51).…”

“…Superoxide and subsequently generated reactive oxygen species (ROS) may act as second messengers, controlling the activity of the trans-acting factor(s) that regulate the transcription of hypoxic genes (2,10,11). The second is cytochrome a 3 of the mitochondrial respiratory chain (12)(13)(14)(15)(16)(17). Although the signaling pathway from cytochrome c oxidase is not yet clearly defined, a recent report (18), which appeared during the revision of this manuscript, suggests that ROS may be involved here too.…”

Oxygen sensing and signaling: impact on the regulation of physiologically important genes

“…As mentioned above, patch clamp experiments indicate that the oxygen sensor in carotid body type I cells resides in the plasma membrane (Ganfornina and López-Barneo, 1991). Nevertheless, several reports have suggested that mitochondria may play a critical role in oxygen sensing by the carotid body (Mulligan et al, 1981;Obeso et al, 1985;Duchen and Biscoe, 1992;Wilson et al, 1994;Lahiri et al, 1995). In view of the extraordinarily rich vascularity and high oxygen consumption of the carotid body, there may be a unique functional role for a mitochondrial oxygen sensor.…”

Immediate and Long-Term Responses of the Carotid Body to High Altitude

“…Thus, deficiency in substrate for the citric acid cycle, and thereby for oxidative phosphorylation, also mimics hypoxia. High levels of mitochondrial inhibitors abolish the oxygen chemosensory response in the carotid body (Lahiri, 2004;Mulligan et al, 1981). It should be noted, however, that the carotid body afferent activity can still, at least transiently, be stimulated by changes in CO 2 /H + (Lahiri, 2004;Mulligan et al, 1981).…”

“…Over the years, studies have resulted in a wide range of proposals for the identity of the oxygen sensor. These proposals included that the sensor is mitochondrial cytochrome oxidase (Mulligan et al, 1981;Wilson et al, 1994), an oxygensensitive K + channel (López-Barneo et al, 1998;2001), NADPH oxidase (Acker, 1994), or other entity (Eyzaguirre and Koyano, 1965a, b, c;Streller et al, 2002). It is not the purpose of the present paper to comprehensively review the extensive literature on the subject.…”