Functional evaluation of carotid body mitochondria in health and heart failure.

Abstract

Heart failure (HF) is a major health concern worldwide affecting millions of people. Decreased ventricular ejection faction and sympathetic overactivation are two of the main hallmarks of HF. One of the principal drivers of sympathetic overactivation are the carotid bodies (CBs). The CB is the main peripheral oxygen sensor, and its efferent output and hypoxic sensitivity are enhanced in HF. While, CBs are an attractive pharmacological target, the development of the therapies targeting CB has been limited due to a lack of understanding of the oxygen-sensing cascade. Previous data suggest that the oxygen sensor is located within mitochondrial complex IV and as result of inhibition of complex IV, there is an increase in reactive oxygen species (ROS) production to evoke a hypoxic response. However, the mitochondrial function has not been directly assessed in health and disease, hence this thesis aimed to address this. In initial experiments, mitochondrial function and composition were assessed in control CBs and compared to the control left ventricular myocardium. Firstly, the complex IV oxygen affinity was shown to be high and the reverse electron transport capacity low. Mitochondrial aerobic capacity was low in the CB, while ROS production rate was high. Interestingly, the expression of mitochondrial genes was high in the CB, while there was a low abundance of mitochondrial complexes. Further experiments showed that the oxygen affinity of CB complex IV and ATP production efficiency due to an increased LEAK respiration are lower in HF. Finally, there was an increase in CB oxidative stress in HF, however there was no increase in mitochondrial ROS production rate. Interestingly, the expression of mitochondrial genes, abundance of mitochondrial complexes and mitochondrial population were all increased in CBs collected from HF animals. Data presented here shows that the CB has a specific metabolic profile suggesting that mitochondrial signalling may be important for CB oxygen sensing. Additionally, a high oxygen sensitivity of CB mitochondria suggests that the oxygen affinity may be modulated by other factors (i.e., nitric oxide) rather than a change in the intrinsic properties of complex IV. Furthermore, ROS may not be a sole mediator of the mitochondrial signalling to the cell membrane in oxygen-sensing cascade. In HF, the increase in mitochondrial gene expression and therefore mitochondrial population suggests that in disease certain metabolic changes occur in the CB. Additionally, a decrease in aerobic capacity and oxygen affinity of complex IV suggest that mitochondria are involved in driving an increase in CB function in HF. However, these data do not support the hypothesis that mitochondria are involved in driving an increase in oxidative stress, indicating that this is potentially solely driven by cytosolic signalling pathways (i.e., angiotensin II signalling). Overall, data presented here supports the hypothesis that mitochondria undergo changes in HF which contribute to driving an enhanced CB function in these patients.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andy Trafford (Supervisor) & Gina Galli (Supervisor)