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09-05-2024 | Original Contribution

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

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

Published in: Basic Research in Cardiology

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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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Metadata
Title
Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43Cre−ER(T)/fl mice by altering the coenzyme Q pool
Authors
Marta Consegal
Elisabet Miró-Casas
Ignasi Barba
Marisol Ruiz-Meana
Javier Inserte
Begoña Benito
Cristina Rodríguez
Freddy G. Ganse
Laura Rubio-Unguetti
Carmen Llorens-Cebrià
Ignacio Ferreira-González
Antonio Rodríguez-Sinovas
Publication date
09-05-2024
Publisher
Springer Berlin Heidelberg
Published in
Basic Research in Cardiology
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI
https://doi.org/10.1007/s00395-024-01052-2
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