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

Standard

Mitochondrial succinate metabolism and reactive oxygen species are important but not essential for eliciting carotid body and ventilatory responses to hypoxia in the rat. / Swiderska, Agnieszka; Coney, Andrew M.; Alzahrani, Abdulaziz A.; Aldossary, Hayyaf S.; Batis, Nikolaos; Ray, Clare J.; Kumar, Prem; Holmes, Andrew P.

In: Antioxidants, Vol. 10, No. 6, 840, 25.05.2021.

Research output: Contribution to journalArticlepeer-review

Harvard

APA

Vancouver

Author

Bibtex

@article{edd9346c8cfa4b10b6be51cb81411b42,
title = "Mitochondrial succinate metabolism and reactive oxygen species are important but not essential for eliciting carotid body and ventilatory responses to hypoxia in the rat",
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.",
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",
author = "Agnieszka Swiderska and Coney, {Andrew M.} and Alzahrani, {Abdulaziz A.} and Aldossary, {Hayyaf S.} and Nikolaos Batis and Ray, {Clare J.} and Prem Kumar and Holmes, {Andrew P.}",
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.",
year = "2021",
month = may,
day = "25",
doi = "10.3390/antiox10060840",
language = "English",
volume = "10",
journal = "Antioxidants",
issn = "2076-3921",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "6",

}

RIS

TY - JOUR

T1 - Mitochondrial succinate metabolism and reactive oxygen species are important but not essential for eliciting carotid body and ventilatory responses to hypoxia in the rat

AU - Swiderska, Agnieszka

AU - Coney, Andrew M.

AU - Alzahrani, Abdulaziz A.

AU - Aldossary, Hayyaf S.

AU - Batis, Nikolaos

AU - Ray, Clare J.

AU - Kumar, Prem

AU - Holmes, Andrew P.

N1 - 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.

PY - 2021/5/25

Y1 - 2021/5/25

N2 - 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.

AB - 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.

KW - Carotid body

KW - Hypoxia

KW - Hypoxic ventilatory response

KW - Mitochondrial reactive oxygen species

KW - Succinate

KW - Succinate dehydrogenase

KW - succinate

KW - hypoxia

KW - carotid body

KW - mitochondrial reactive oxygen species

KW - hypoxic ventilatory response

KW - succinate dehydrogenase

UR - http://www.scopus.com/inward/record.url?scp=85106430804&partnerID=8YFLogxK

U2 - 10.3390/antiox10060840

DO - 10.3390/antiox10060840

M3 - Article

C2 - 34070267

VL - 10

JO - Antioxidants

JF - Antioxidants

SN - 2076-3921

IS - 6

M1 - 840

ER -