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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.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 2024 Aug; Vol. 119 (4), pp. 673-689. Date of Electronic Publication: 2024 May 09. - Publication Year :
- 2024
-
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 Cx43 <superscript>Cre-ER(T)/fl</superscript> 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 <superscript>fl/fl</superscript> mice and Cx43 <superscript>Cre-ER(T)/fl</superscript> 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 <superscript>Cre-ER(T)/fl</superscript> mice treated with 4OHT had a smaller infarct size after IR compared to Cx43 <superscript>fl/fl</superscript> , 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.<br /> (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)
- Subjects :
- Animals
Mice
Electron Transport drug effects
Membrane Potential, Mitochondrial drug effects
Myocardial Reperfusion Injury metabolism
Myocardial Reperfusion Injury pathology
Myocardial Reperfusion Injury genetics
Male
Ubiquinone analogs & derivatives
Ubiquinone pharmacology
Ubiquinone metabolism
Ubiquinone deficiency
Mitochondria, Heart metabolism
Mitochondria, Heart pathology
Mitochondria, Heart drug effects
Connexin 43 metabolism
Connexin 43 genetics
Mice, Knockout
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1435-1803
- Volume :
- 119
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 38724619
- Full Text :
- https://doi.org/10.1007/s00395-024-01052-2