Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat.

Agnieszka Swiderska,Andrew P Holmes,Nikolaos Batis,Andrew M Coney,Abdulaziz A Alzahrani,Clare J Ray,Prem Kumar,Hayyaf S Aldossary

doi:10.3390/antiox10060840

Abstract

Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O2-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The objective of this study was to evaluate if ex vivo intact CB nerve activity and in vivo whole body ventilatory responses to hypoxia were modified by alterations in succinate metabolism and mitochondrial ROS (mitoROS) generation in the rat. Application of diethyl succinate (DESucc) caused concentration-dependent increases in chemoafferent frequency measuring approximately 10–30% of that induced by severe hypoxia. Inhibition of mitochondrial succinate metabolism by dimethyl malonate (DMM) evoked basal excitation and attenuated the rise in chemoafferent activity in hypoxia. However, approximately 50% of the response to hypoxia was preserved. MitoTEMPO (MitoT) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SKQ1) (mitochondrial antioxidants) decreased chemoafferent activity in hypoxia by approximately 20–50%. In awake animals, MitoT and SKQ1 attenuated the rise in respiratory frequency during hypoxia, and SKQ1 also significantly blunted the overall hypoxic ventilatory response (HVR) by approximately 20%. Thus, whilst the data support a role for succinate and mitoROS in CB and whole body O2-sensing in the rat, they are not the sole mediators. Treatment of the CB with mitochondrial selective antioxidants may offer a new approach for treating CB-related cardiovascular–respiratory disorders.

Highlights

The ability for humans to sense and respond to a fall in blood oxygen has never been so apparent as in the current COVID-19 pandemic, in which millions of people have experienced this life-threatening stressor [1]
Prolonged exposure of the carotid body (CB) to 5 mM diethyl succinate (DESucc) demonstrated that the chemoafferent frequency did not continue to rise, but rather peaked at 5 min, remained elevated at 15 min before returning to, or slightly below baseline (Figure 1c)
Even at the highest concentrations, the response to DESucc was relatively modest compared to hypoxia (Figure 2a)

Summary

Introduction

The ability for humans to sense and respond to a fall in blood oxygen (hypoxia/hypoxaemia) has never been so apparent as in the current COVID-19 pandemic, in which millions of people have experienced this life-threatening stressor [1]. Antioxidants 2021, 10, 840 cell has an extraordinarily high sensitivity to O2 , with its activity increasing exponentially from mild levels of hypoxia [4]. The CB activates numerous critical protective reflexes including hyperventilation, tachycardia, systemic vasoconstriction, and adrenaline release [5,6]. These reflexes are essential to preserve enough O2 delivery to the brain and vital organs, helping to support survival. One of the most longstanding hypotheses is that during hypoxia, CB mitochondrial electron transport is inhibited [8,9]

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Conclusion