Molecular Mechanisms of Acute Oxygen Sensing by Arterial Chemoreceptor Cells. Role of Hif2α

Abstract

Carotid body glomus cells are multimodal arterial chemoreceptors able to sense and integrate changes in several physical and chemical parameters in the blood. These cells are also essential for O₂ homeostasis. Glomus cells are prototypical peripheral O₂ sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation). The mechanisms underlying acute O₂ sensing by glomus cells have been elusive. Using a combination of mouse genetics and single-cell optical and electrophysiological techniques, it has recently been shown that activation of glomus cells by hypoxia relies on the generation of mitochondrial signals (NADH and reactive oxygen species), which modulate membrane ion channels to induce depolarization, Ca²⁺ influx, and transmitter release. The special sensitivity of glomus cell mitochondria to changes in O₂ tension is due to Hif2α-dependent expression of several atypical mitochondrial subunits, which are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O₂ availability. A mitochondrial-to-membrane signaling model of acute O₂ sensing has been proposed, which explains existing data and provides a solid foundation for future experimental tests. This model has also unraveled new molecular targets for pharmacological modulation of carotid body activity potentially relevant in the treatment of highly prevalent medical conditions.

Keywords: acute O2 sensing; carotid body; electron transport chain; glomus cells; ion channels; mechanism of disease; mitochondrial signaling; paraganglioma.

Figure 1

Structural and functional properties of carotid arterial chemoreceptors. (A) Location and innervation of the carotid body (CB). (B) Schematic representation of a CB glomerulus with indication of the various structural components and cell types. (C) Schematic representation of CB glomus cell activation by several stimuli. (D,E) Hyperbolic relationships between cytosolic Ca²⁺ (inset in D) and catecholamine release (inset in E) in single glomus cells as a function of oxygen tension in the external solution. Hypoxia-induced increase in cytosolic Ca²⁺ depends on extracellular Ca²⁺ influx (D). (F) Relationship between firing frequency in afferent fibers of the sinus nerve as a function of blood oxygen tension. (A–C) Modified from Ortega-Saenz and Lopez-Barneo (2020). (D,E) Modified from Montoro et al. (1996) and Ortega-Saenz et al. (2006). (F) Modified from Lopez-Barneo (1996).

Figure 2

Selective inhibition of acute oxygen sensing by arterial chemoreceptors in mitochondrial complex I (MCI)-deficient mice. (A) Ventilatory response to hypoxia in wild type (top) and Ndufs2-deficient (bottom) mice. (B) Changes in cytosolic Ca²⁺ in single wild type (top) and Ndufs2-deficient (bottom) glomus cells induced by depolarization (40 mM K⁺), hypoxia (Hx, ~15 mm Hg), 0 glucose (0 glu), and hypercapnia (switching from 5 to 10% CO₂). (C) Scheme of the electron transport chain illustrating the mitochondria-to-membrane signaling model of acute O₂ sensing by glomus cells. Changes in chemical equilibrium induced by hypoxia (Hx) are represented in red. (D) Changes in NADH autofluorescence in single glomus cells from wild type and Ndufs2-deficient mice during exposure to hypoxia. Relationship between NADH levels and extracellular oxygen tension. (E) Measurement of reactive oxygen species (ROS) at the mitochondrial intermembrane space in single glomus cells from wild type and Ndufs2-deficient mice. Relationship between ROS levels and extracellular oxygen tension. Modified from Fernandez-Aguera et al. (2015) and Arias-Mayenco et al. (2018).

Figure 3

Selective inhibition of carotid body glomus cell responsiveness to hypoxia in Hif2α‐ and Cox4i2-deficient mice. (A) Changes in cytosolic Ca²⁺ in single wild type (left), Hif2α-deficient (center), and Cox4i2-deficient (right) glomus cells induced by depolarization (40 mM K⁺), hypoxia (Hx, ~15 mm Hg), and hypercapnia (switching from 5 to 10% CO₂). (B) Changes in NADH autofluorescence in single glomus cells from wild type and Hif2α-deficient mice during exposure to hypoxia. (C) Measurement of ROS at the mitochondrial intermembrane space (IMS) in single glomus cells from wild type and Hif2α-deficient mice. (D) Measurement of ROS at the mitochondrial matrix in single glomus cells from wild type and Hif2α-deficient mice. In B-D, response to rotenone (0.5–1 μM) was tested to show the normal function of MCI. Modified from Moreno-Dominguez et al. (2020).

Figure 4

Mitochondria-to-membrane signaling model of acute oxygen sensing by glomus cells. (A) Scheme illustrating the mitochondrial signals (NADH and ROS) generated upon exposure to hypoxia and their interaction with membrane ion channels. Modified from Moreno-Dominguez et al. (2020). (B) Model of chemosensory transduction by O₂-sensing glomus cells in the carotid body. Modified from Fernandez-Aguera et al. (2015).