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Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43Cre−ER(T)/fl mice by altering the coenzyme Q pool

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Abstract

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 Cx43Cre−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 Cx43fl/fl mice and Cx43Cre−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 Cx43Cre−ER(T)/fl mice treated with 4OHT had a smaller infarct size after IR compared to Cx43fl/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.

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Data availability

The authors declare that the data supporting the findings are available within the paper. Any remaining data that support the results of the study will be available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by the Spanish Ministry of Economy and Competitiveness.

Funding

Instituto de Salud Carlos III (grants PI23/00260, PI22/00513, PI17/01397 and CIBERCV) and the Spanish Society of Cardiology (Proyectos de la FEC para Investigación Básica en Cardiología 2018, Sociedad Española de Cardiología), and was cofinanced by the European Regional Development Fund (ERDF–FEDER, a way to build Europe). Antonio Rodríguez-Sinovas has a consolidated Miguel Servet contract.

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Authors and Affiliations

  1. 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

    Marta Consegal, Elisabet Miró-Casas, Marisol Ruiz-Meana, Javier Inserte, Begoña Benito, Freddy G. Ganse, Laura Rubio-Unguetti, Carmen Llorens-Cebrià, Ignacio Ferreira-González & Antonio Rodríguez-Sinovas

  2. Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain

    Marta Consegal, Elisabet Miró-Casas, Marisol Ruiz-Meana, Javier Inserte, Begoña Benito, Cristina Rodríguez, Freddy G. Ganse, Laura Rubio-Unguetti, Carmen Llorens-Cebrià & Antonio Rodríguez-Sinovas

  3. Faculty of Medicine, University of Vic - Central University of Catalonia (UVicUCC), Can Baumann. Ctra. de Roda, 70, 08500, Vic, Spain

    Ignasi Barba

  4. Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain

    Cristina Rodríguez

  5. Centro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública, CIBERESP, Instituto de Salud Carlos III, Madrid, Spain

    Ignacio Ferreira-González

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  1. Marta Consegal
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  12. Antonio Rodríguez-Sinovas
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Contributions

All authors contributed to the study. ARS and IFG designed the experiments. MC, EMC and MRM performed studies in isolated mitochondria (ROS production, CoQ analysis), including data collection and analysis. IB and MC performed and analyzed 1H-NMR spectroscopy. MC, JI, BB and CR prepared, collected the data and analyzed those studies addressing ischemia–reperfusion injury in isolated hearts. EMC, FGG and CLC analyzed expression of proteins by conventional Western blot. EMC, FGG and LRU conducted NAD/NADH analysis. ARS, IFG, MRM, BB, CR and JI guided data interpretation. ARS secured funding. The first draft was written by ARS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ignacio Ferreira-González or Antonio Rodríguez-Sinovas.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The present study conforms to the NIH Guide for the Care and Use of Laboratory Animals (NIH publications Nº. 85–23, revised 1996), and was performed in accordance with European legislation (Directive 2010/63/UE). The study was approved by the Ethics Committee of our institution (CEEA 22.20).

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Consegal, M., Miró-Casas, E., Barba, I. et al. Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43Cre−ER(T)/fl mice by altering the coenzyme Q pool. Basic Res Cardiol (2024). https://doi.org/10.1007/s00395-024-01052-2

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