Abstract
Classically considered a by-product of anaerobic metabolism, lactate is now viewed as a fundamental fuel for oxidative phosphorylation in mitochondria, and preferred over glucose by many tissues. Lactate is also a signaling molecule of increasing medical relevance. Lactate levels in the blood can increase in both normal and pathophysiological conditions (e.g., hypoxia, physical exercise, or sepsis), however the manner by which these changes are sensed and induce adaptive responses is unknown. Here we show that the carotid body (CB) is essential for lactate homeostasis and that CB glomus cells, the main oxygen sensing arterial chemoreceptors, are also lactate sensors. Lactate is transported into glomus cells, leading to a rapid increase in the cytosolic NADH/NAD+ ratio. This in turn activates membrane cation channels, leading to cell depolarization, action potential firing, and Ca2+ influx. Lactate also decreases intracellular pH and increases mitochondrial reactive oxygen species production, which further activates glomus cells. Lactate and hypoxia, although sensed by separate mechanisms, share the same final signaling pathway and jointly activate glomus cells to potentiate compensatory cardiorespiratory reflexes.
Highlights
Considered a by-product of anaerobic metabolism, lactate is viewed as a fundamental fuel for oxidative phosphorylation in mitochondria, and preferred over glucose by many tissues
We tested whether the carotid body (CB) plays any role in lactate homeostasis by monitoring hypoxia-induced lactatemia in wild type mice compared to mice insensitive to hypoxia due to deficient CB function
We used two mouse models previously studied in our laboratory: tyrosine hydroxylase (TH)-HIF2α, with embryonic ablation of the gene Epas[1] in sympathoadrenal cells and exhibiting CB atrophy and strong inhibition of the HVR33 (Supplementary Fig. 1), and ERT2-HIF2α, with ubiquitous conditional ablation of Epas[1] and showing normal CB development but selective abolition of responsiveness to hypoxia in adulthood[34]
Summary
We tested whether the CB plays any role in lactate homeostasis by monitoring hypoxia-induced lactatemia in wild type mice (control) compared to mice insensitive to hypoxia due to deficient CB function To this end, we used two mouse models previously studied in our laboratory: TH-HIF2α, with embryonic ablation of the gene Epas[1] (coding HIF2α) in sympathoadrenal (tyrosine hydroxylase-positive) cells and exhibiting CB atrophy and strong inhibition of the HVR33 (Supplementary Fig. 1), and ERT2-HIF2α, with ubiquitous conditional ablation of Epas[1] and showing normal CB development but selective abolition of responsiveness to hypoxia in adulthood[34]. Lactatemia elicited by breathing 10% O2, was much higher in CB-deficient mice (~30% and ~90% increase in TH-HIF2α and ERT2-HIF2α strains, respectively) than in controls (Fig. 1d) These data indicate that hypercapnia induces, as hypoxia, CB activation[27] and hyperventilation it is not accompanied by lactatemia. Control of the lactateinduced acidification signal was obtained by exposure of the cells to CO2, which strongly acidifies the cytosol due to its conversion to carbonic acid by carbonic anhydrase present in CB glomus cells[27]
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