Enhanced hypoxic ventilatory response is accompanied by a decrease in carotid body mitochondrial oxygen affinity in heart failure
- 1University of Manchester
Abstract
Carotid bodies (CBs), the main peripheral oxygen sensors, play a significant role in sympathetic overdrive in heart failure (HF), resulting in worse clinical outcomes. Whilst CBs are an attractive therapeutic target, the development of CB focused therapies has been limited as the oxygen sensing mechanism is not fully understood. It has been hypothesised that the oxygen sensor is part of mitochondrial complex IV, and reactive oxygen species (ROS) signalling plays a crucial role in the oxygen sensing cascade. However, changes to CB mitochondrial function have never been determined in HF. Hence, we aimed to address this gap by characterising CB mitochondrial function and ROS production using a rapid pacing ovine model of HF. The hypoxic ventilatory response (HVR) and autonomic function were assessed pre- and post HF induction. Tissue homogenates were prepared from whole CBs from control and HF and utilised to measure kinetics of mitochondrial oxygen affinity, respiration and H2O2 production rates by high-resolution respirometry. In HF, HVR and sympathetic drive were increased, while complex IV oxygen affinity was decreased. Despite an increase in abundance of mitochondrial complexes, no changes in mitochondrial respiration or H2O2 production were observed. However, aconitase activity and lipid peroxidation level were increased in HF. Overall, these results suggest that the CB mitochondrial function is altered in HF, and decreased CB mitochondrial oxygen affinity may suggest a higher complex IV oxygen sensitivity. Higher oxygen sensitivity accompanied by an increased oxidative stress may be key drivers of CB overactivity and therefore autonomic imbalance in HF.
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BibTeX
@misc{swiderska2026enhanced,
title = {{Enhanced hypoxic ventilatory response is accompanied by a decrease in carotid body mitochondrial oxygen affinity in heart failure}},
author = {A. Swiderska and M. Obeidat and G. W. Madders and A. S. Whitley and J. C. Burke and M. Lin and G. L. J. Galli and A. W. Trafford},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764874},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764874v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Enhanced hypoxic ventilatory response is accompanied by a decrease in carotid body mitochondrial oxygen affinity in heart failure
AU - A. Swiderska
AU - M. Obeidat
AU - G. W. Madders
AU - A. S. Whitley
AU - J. C. Burke
AU - M. Lin
AU - G. L. J. Galli
AU - A. W. Trafford
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764874
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764874v1
AB - Carotid bodies (CBs), the main peripheral oxygen sensors, play a significant role in sympathetic overdrive in heart failure (HF), resulting in worse clinical outcomes. Whilst CBs are an attractive therapeutic target, the development of CB focused therapies has been limited as the oxygen sensing mechanism is not fully understood. It has been hypothesised that the oxygen sensor is part of mitochondrial complex IV, and reactive oxygen species (ROS) signalling plays a crucial role in the oxygen sensing cascade. However, changes to CB mitochondrial function have never been determined in HF. Hence, we aimed to address this gap by characterising CB mitochondrial function and ROS production using a rapid pacing ovine model of HF. The hypoxic ventilatory response (HVR) and autonomic function were assessed pre- and post HF induction. Tissue homogenates were prepared from whole CBs from control and HF and utilised to measure kinetics of mitochondrial oxygen affinity, respiration and H2O2 production rates by high-resolution respirometry. In HF, HVR and sympathetic drive were increased, while complex IV oxygen affinity was decreased. Despite an increase in abundance of mitochondrial complexes, no changes in mitochondrial respiration or H2O2 production were observed. However, aconitase activity and lipid peroxidation level were increased in HF. Overall, these results suggest that the CB mitochondrial function is altered in HF, and decreased CB mitochondrial oxygen affinity may suggest a higher complex IV oxygen sensitivity. Higher oxygen sensitivity accompanied by an increased oxidative stress may be key drivers of CB overactivity and therefore autonomic imbalance in HF.
ER -