Mitochondrial succinate metabolism and reactive oxygen species are important but not essential for eliciting carotid body and ventilatory responses to hypoxia in the rat

Research output: Contribution to journalArticlepeer-review

Authors

  • Agnieszka Swiderska
  • Abdulaziz A. Alzahrani
  • Hayyaf S. Aldossary

External organisations

  • University of Birmingham

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.

Bibliographic note

Funding Information: This work was funded by a Wellcome Trust Institutional Strategic Support Fund award to A.P.H., a Scholarship from Umm Al-Qura University (Makkah, Saudi Arabia) provided to A.A.A. through the Saudi Arabian Cultural Bureau in London and a Scholarship from King Saud bin Abdu-laziz University for Health Sciences (Riyadh, Saudi Arabia) provided to H.S.A. through the Saudi Arabian Cultural Bureau in London.” and “The APC was funded by University of Birmingham, UK.” Institutional Review Board Statement: All procedures were performed in accordance with UK Animals (Scientific Procedures) Act 1986 and approved by the UK Home Office (PPL number PF4C074AD) and by the Animal Welfare and Ethical Review Body (AWERB) at the University of Birmingham.

Details

Original languageEnglish
Article number840
Number of pages20
JournalAntioxidants
Volume10
Issue number6
Publication statusPublished - 25 May 2021

Keywords

  • Carotid body, Hypoxia, Hypoxic ventilatory response, Mitochondrial reactive oxygen species, Succinate, Succinate dehydrogenase, succinate, hypoxia, carotid body, mitochondrial reactive oxygen species, hypoxic ventilatory response, succinate dehydrogenase