Is Carotid Body Physiological O2 Sensitivity Determined by a Unique Mitochondrial Phenotype?

Abstract

The mammalian carotid body (CB) is the primary arterial chemoreceptor that responds to acute hypoxia, initiating systemic protective reflex responses that act to maintain O2 delivery to the brain and vital organs. The CB is unique in that it is stimulated at O2 levels above those that begin to impact on the metabolism of most other cell types. Whilst a large proportion of the CB chemotransduction cascade is well defined, the identity of the O2 sensor remains highly controversial. This short review evaluates whether the mitochondria can adequately function as acute O2 sensors in the CB. We consider the similarities between mitochondrial poisons and hypoxic stimuli in their ability to activate the CB chemotransduction cascade and initiate rapid cardiorespiratory reflexes. We evaluate whether the mitochondria are required for the CB to respond to hypoxia. We also discuss if the CB mitochondria are different to those located in other non-O2 sensitive cells, and what might cause them to have an unusually low O2 binding affinity. In particular we look at the potential roles of competitive inhibitors of mitochondrial complex IV such as nitric oxide in establishing mitochondrial and CB O2-sensitivity. Finally, we discuss novel signaling mechanisms proposed to take place within and downstream of mitochondria that link mitochondrial metabolism with cellular depolarization.

Carotid Body Type-I Cells Under Chronic Sustained Hypoxia: Focus on Metabolism and Membrane Excitability

“…Even though some reports postulate a null or small effect of ATP on these conductances ( Xu et al, 2005 ) one of the earliest proposition, the “metabolic hypothesis”, states that CB oxygen sensing is mediated by oxidative phosphorylation, supported by the fact that virtually all metabolic poisons or oxidative phosphorylation inhibitors induce CB type-I cell excitation ( Mulligan and Lahiri, 1982 ; Buerk et al, 1994 ; Wilson et al, 1994 ; Buckler and Turner, 2013 ). This response is normally triggered by potassium conductance(s) inhibition leading to the depolarization of the type-I cell membrane, reinforcing the notion that low PO 2 trigger potassium current blockage ( Figure 1 , see also Holmes et al, 2018 ). In this regard, it has been postulated that CB-mitochondria express a particular subtype of cytochrome a3 – the functional core of mitochondrion complex IV – which is at least seven times more sensitive to a drop in the PO 2 , further supporting a pivotal role of mitochondrial metabolism on CB-type-I cell excitation (for a full revision on this matter see Holmes et al, 2018 in this same research topic).…”

“…This response is normally triggered by potassium conductance(s) inhibition leading to the depolarization of the type-I cell membrane, reinforcing the notion that low PO 2 trigger potassium current blockage ( Figure 1 , see also Holmes et al, 2018 ). In this regard, it has been postulated that CB-mitochondria express a particular subtype of cytochrome a3 – the functional core of mitochondrion complex IV – which is at least seven times more sensitive to a drop in the PO 2 , further supporting a pivotal role of mitochondrial metabolism on CB-type-I cell excitation (for a full revision on this matter see Holmes et al, 2018 in this same research topic).…”

“…Accordingly, in absence of ATP, TASK channel activity decreases in ∼50 % in inside-out patches ( Williams and Buckler, 2004 ; Varas et al, 2007 ). Thus, ATP production seems to be central in regulating the activity of TASK-like and other potassium channels such as maxi-K ( Williams and Buckler, 2004 ; Varas et al, 2007 ; Holmes et al, 2018 ). Even though some reports postulate a null or small effect of ATP on these conductances ( Xu et al, 2005 ) one of the earliest proposition, the “metabolic hypothesis”, states that CB oxygen sensing is mediated by oxidative phosphorylation, supported by the fact that virtually all metabolic poisons or oxidative phosphorylation inhibitors induce CB type-I cell excitation ( Mulligan and Lahiri, 1982 ; Buerk et al, 1994 ; Wilson et al, 1994 ; Buckler and Turner, 2013 ).…”

Chronic hypoxia changes gene expression profile of primary rat carotid body cells: consequences on the expression of NOS isoforms and ET-1 receptors

“…At low concentrations, NO is a tonic inhibitor of the hypoxic CB's chemoreception, reducing L-type Ca 2ϩ currents in glomus cells and consequently the frequency of chemosensory discharge (51,53,54,64,87). The same high concentration of the NO donor that reduces the CB chemosensory excitation in hypoxia causes CB chemoreception excitation in normoxia (64), suggesting that NO acts as a modulator of the mitochondrial-mediated chemosensory response (44,45,64).…”

β-Adrenoceptor blockade prevents carotid body hyperactivity and elevated vascular sympathetic nerve density induced by chronic intermittent hypoxia

“…There is evidence that mitochondrial ROS is increased in the CB and other tissues in response to CIH [52,69]. Precisely how CIH and potentially Adr impact on CB mitochondrial function could be a key area for future consideration, especially given the important suggested role of mitochondria in the CB [2,5,20]. It will be of interest to establish the point at which these This is the first study to demonstrate protein expression of β 1 and β 2 -adrenoceptor -subtypes in the CB type I cell.…”