Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise

Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes; however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G139...

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Autores: Vujic, A, Koo, A, Bidault, G, Miljkovic, JLJ, James, AM, Dannhorn, A, Duan, XW, Davis, LM, Abe, J, Valadares, J, Lee, JJ, Diaz-Vegas, A, Turner, K, Goodwin, R, Fazakerley, DJ, Vidal-Puig, A, Murphy, MP, Krieg, T
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Centro de Investigación Principe Felipe (CIPF)
Repositorio:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
OAI Identifier:oai:cipf.fundanetsuite.com:p4530
Acesso em linha:https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4530
Access Level:acceso abierto
Palavra-chave:exercise
HFpEF
lipid metabolism
mitochondria
RET-ROS
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repository_id_str
spelling Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exerciseVujic, AKoo, ABidault, GMiljkovic, JLJJames, AMDannhorn, ADuan, XWDavis, LMAbe, JValadares, JLee, JJDiaz-Vegas, ATurner, KGoodwin, RFazakerley, DJVidal-Puig, AMurphy, MPKrieg, TexerciseHFpEFlipid metabolismmitochondriaRET-ROSCentral to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes; however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G13997A), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in wild-type but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (CD36, Cpt1b, Acly, Fas, Elovl6, and Scd1) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 wk of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism.AMER PHYSIOLOGICAL SOC2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4530AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGYISSN: 03636135ISSNe: 15221539reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)instname:Centro de Investigación Principe Felipe (CIPF)Inglésinfo:eu-repo/semantics/openAccessoai:cipf.fundanetsuite.com:p45302026-06-17T11:19:47Z
dc.title.none.fl_str_mv Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
title Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
spellingShingle Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
Vujic, A
exercise
HFpEF
lipid metabolism
mitochondria
RET-ROS
title_short Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
title_full Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
title_fullStr Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
title_full_unstemmed Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
title_sort Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise
dc.creator.none.fl_str_mv Vujic, A
Koo, A
Bidault, G
Miljkovic, JLJ
James, AM
Dannhorn, A
Duan, XW
Davis, LM
Abe, J
Valadares, J
Lee, JJ
Diaz-Vegas, A
Turner, K
Goodwin, R
Fazakerley, DJ
Vidal-Puig, A
Murphy, MP
Krieg, T
author Vujic, A
author_facet Vujic, A
Koo, A
Bidault, G
Miljkovic, JLJ
James, AM
Dannhorn, A
Duan, XW
Davis, LM
Abe, J
Valadares, J
Lee, JJ
Diaz-Vegas, A
Turner, K
Goodwin, R
Fazakerley, DJ
Vidal-Puig, A
Murphy, MP
Krieg, T
author_role author
author2 Koo, A
Bidault, G
Miljkovic, JLJ
James, AM
Dannhorn, A
Duan, XW
Davis, LM
Abe, J
Valadares, J
Lee, JJ
Diaz-Vegas, A
Turner, K
Goodwin, R
Fazakerley, DJ
Vidal-Puig, A
Murphy, MP
Krieg, T
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv exercise
HFpEF
lipid metabolism
mitochondria
RET-ROS
topic exercise
HFpEF
lipid metabolism
mitochondria
RET-ROS
description Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes; however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G13997A), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in wild-type but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (CD36, Cpt1b, Acly, Fas, Elovl6, and Scd1) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 wk of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4530
url https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4530
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv AMER PHYSIOLOGICAL SOC
publisher.none.fl_str_mv AMER PHYSIOLOGICAL SOC
dc.source.none.fl_str_mv AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
ISSN: 03636135
ISSNe: 15221539
reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
instname:Centro de Investigación Principe Felipe (CIPF)
instname_str Centro de Investigación Principe Felipe (CIPF)
reponame_str r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
collection r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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