Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43 Cre-ER(T)/fl mice by altering the coenzyme Q pool.

Autor: Consegal M; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Miró-Casas E; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Barba I; Faculty of Medicine, University of Vic - Central University of Catalonia (UVicUCC), Can Baumann. Ctra. de Roda, 70, 08500, Vic, Spain., Ruiz-Meana M; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Inserte J; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Benito B; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Rodríguez C; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.; Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain., Ganse FG; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Rubio-Unguetti L; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Llorens-Cebrià C; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain., Ferreira-González I; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. nachoferreira@secardiologia.es.; Centro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública, CIBERESP, Instituto de Salud Carlos III, Madrid, Spain. nachoferreira@secardiologia.es., Rodríguez-Sinovas A; Cardiovascular Diseases Research Group, Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. antonio.rodriguez.sinovas@vhir.org.; Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. antonio.rodriguez.sinovas@vhir.org.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2024 Aug; Vol. 119 (4), pp. 673-689. Date of Electronic Publication: 2024 May 09.
DOI: 10.1007/s00395-024-01052-2
Abstrakt: Succinate accumulates during myocardial ischemia and is rapidly oxidized during reperfusion, leading to reactive oxygen species (ROS) production through reverse electron transfer (RET) from mitochondrial complex II to complex I, and favoring cell death. Given that connexin 43 (Cx43) modulates mitochondrial ROS production, we investigated whether Cx43 influences RET using inducible knock-out Cx43 Cre-ER(T)/fl mice. Oxygen consumption, ROS production, membrane potential and coenzyme Q (CoQ) pool were analyzed in subsarcolemmal (SSM, expressing Cx43) and interfibrillar (IFM) cardiac mitochondria isolated from wild-type Cx43 fl/fl mice and Cx43 Cre-ER(T)/fl knock-out animals treated with 4-hydroxytamoxifen (4OHT). In addition, infarct size was assessed in isolated hearts from these animals submitted to ischemia-reperfusion (IR), and treated or not with malonate, a complex II inhibitor attenuating RET. Succinate-dependent ROS production and RET were significantly lower in SSM, but not IFM, from Cx43-deficient animals. Mitochondrial membrane potential, a RET driver, was similar between groups, whereas CoQ pool (2.165 ± 0.338 vs. 4.18 ± 0.55 nmol/mg protein, p < 0.05) and its reduction state were significantly lower in Cx43-deficient animals. Isolated hearts from Cx43 Cre-ER(T)/fl mice treated with 4OHT had a smaller infarct size after IR compared to Cx43 fl/fl , despite similar concentration of succinate at the end of ischemia, and no additional protection by malonate. Cx43 deficiency attenuates ROS production by RET in SSM, but not IFM, and was associated with a decrease in CoQ levels and a change in its redox state. These results may partially explain the reduced infarct size observed in these animals and their lack of protection by malonate.
(© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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