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Mitochondrial connexin43 and mitochondrial KATP channels modulate triggered arrhythmias in mouse ventricular muscle

  • Ion Channels, Receptors and Transporters
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Abstract

Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. To generate cardiac-specific Cx43-deficient (cCx43−/−) mice, Cx43flox/flox mice were crossed with α-MHC (Myh6)-cre+/− mice. The resulting offspring, Cx43flox/flox/Myh6-cre+/− mice (cCx43−/− mice) and their littermates (cCx43+/+ mice), were used. Trabeculae were dissected from the right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from the ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2′,7′-dichlorofluorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methyl ester (TMRM), and Ca2+ spark frequency with fluo-4 and confocal microscopy in cardiomyocytes. ROS production within the mitochondria was estimated with MitoSoxRed and mitochondrial Ca2+ with rhod-2 in trabeculae. Diazoxide was used to activate mitochondrial KATP. Most of cCx43−/− mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+ mice but not in cCx43−/− mice. In cCx43−/− mice, the [Ca2+]o,min was lower, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were higher. TMRM fluorescence was more decreased in cCx43−/− mice. Most of these changes were suppressed by diazoxide. In addition, in cCx43−/− mice, antioxidant peptide SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o,min. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to depolarization of mitochondrial membrane potential, an increase in mitochondrial Ca2+, and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (H. Sato, No. 19K17548; M. Miura, No. 19K07298, No 22K06839).

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  1. Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8574, Japan

    Haruka Sato, Masami Nishiyama, Natsuki Morita, Wakako Satoh, Taiki Hasegawa, Yuka Someya, Tsuyoshi Okumura, Sana Koyama, Chiyohiko Shindoh & Masahito Miura

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Contributions

MM and HS conceived the idea and designed the animal experiments; MN, NM, WS, TH, YS, TO, and SK conducted animal and laboratory experiments and analyzed the data; MM, CS, and HS interpreted results and experiments; MM and HS prepared figures; MM and HS have drafted the manuscript.

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Correspondence to Masahito Miura.

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Sato, H., Nishiyama, M., Morita, N. et al. Mitochondrial connexin43 and mitochondrial KATP channels modulate triggered arrhythmias in mouse ventricular muscle. Pflugers Arch - Eur J Physiol 475, 477–488 (2023). https://doi.org/10.1007/s00424-023-02789-w

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