Are Multiple Mitochondrial Related Signalling Pathways Involved in Carotid Body Oxygen Sensing?

Abstract

It is generally acknowledged that the carotid body (CB) type I cell mitochondria are unique, being inhibited by relatively small falls in PaO2 well above those known to inhibit electron transport in other cell types. This feature is suggested to allow for the CB to function as an acute O2 sensor, being stimulated and activating systemic protective reflexes before the metabolism of other cells becomes compromised. What is less clear is precisely how a fall in mitochondrial activity links to type I cell depolarisation, a process that is required for initiation of the chemotransduction cascade and post-synaptic action potential generation. Multiple mitochondrial/metabolic signalling mechanisms have been proposed including local generation of mitochondrial reactive oxygen species (mitoROS), a change in mitochondrial/cellular redox status, a fall in MgATP and an increase in lactate. Although each mechanism is based on compelling experimental evidence, they are all not without question. The current review aims to explore the importance of each of these signalling pathways in mediating the overall CB response to hypoxia. We suggest that there is unlikely to be a single mechanism, but instead multiple mitochondrial related signalling pathways are recruited at different PaO2s during hypoxia. Furthermore, it still remains to be determined if mitochondrial signalling acts independently or in partnership with extra-mitochondrial O2-sensors.

Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication

“…Fourth, an alternative potential mechanism by which glyoxylate improves rebreathing and blood oxygen levels is by an effect on the carotid body and ventilatory responses. It has been shown that ROS, NADH, pH, and other factors affect voltage-dependent potassium channels on the carotid body thereby modulating chemostimulation and ventilatory responses ( Holmes et al , 2022 ). Future studies are required to determine if glyoxylate-mediated modulation of NAD+/NADH and/or redox state, or other actions of glyoxylate in the carotid body influence carotid body function.…”

The Thirty-Fifth Anniversary of K+ Channels in O2 Sensing: What We Know and What We Don’t Know

“…In addition to changes in cell energy status, other mitochondrial signaling mechanisms linking altered mitochondrial metabolism in hypoxia and CB activation have been proposed, including the local generation of mitochondrial ROS (mitoROS) [152,153], changes in redox status [16] and increases in lactate production [154]. All of them are supported by several key observations; for a recent and comprehensive review, see [155].…”

“…There has been relatively little discussion of the possibility that multiple O 2 -sensing systems acting via K + channels may coexist in PASMCs, although Wolin and colleagues have proposed that the response to hypoxia in these cells involves diverse effects on cell redox pathways acting through various effectors such as protein kinase G and Rho kinase [272]. In contrast, it has often been proposed that more than one mechanism of O 2 sensing coexists in CBCC, and might be more or less important at different levels of hypoxia [155,170,273], and the recent study by Swiderska et al [161] which presented evidence that increased succinate-dependent mitochondrial ROS production makes a significant but limited contribution to O 2 sensing in rat CB represents a promising attempt to begin to establish the relative importance of the component mechanisms mediating the hypoxia response.…”

Volatile Anesthetics and O2 Activate TASK-1/3 by Weak H-Bonding with X-Gate Uncharged Arg-245: The Major Molecular Mechanism for Carotid Body Hypoxic Sensitivity and Further Insights into Fighter Pilot +Gz-Induced LOC

“…110 One thought is that this involves alterations in the electron-transport-chain (ECT) during oxidative phosphorylation in mitochondria positioned close to TASK-1/3 channels. 116,117 However, the very fast closure of these channels in response to a drop in P O2 suggests that perhaps a more direct mechanism is involved. Let's look more closely at VLRFM/LT.…”

“…173,174 However, more recently it was concluded that H 2 S signaling was not a major factor in TASK sensitivity to hypoxic conditions. 175 Holmes et al 117 have published an excellent review of the various proposed mechanisms connecting mitochondrial function to (ultimately) TASK 1/3 inhibition and the resulting carotid body response to hypoxia. Variability in mitochondrial P O2 responsiveness at different locations has also been reviewed.…”