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Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart

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Abstract

Mitochondrial connexin 43 (Cx43) plays a key role in cardiac cytoprotection caused by repeated exposure to short periods of non-lethal ischemia/reperfusion, a condition known as ischemic preconditioning. Cx43 also forms calcium (Ca2+)-permeable hemichannels that may potentially lead to mitochondrial Ca2+ overload and cell death. Here, we studied the role of Cx43 in facilitating mitochondrial Ca2+ entry and investigated its downstream consequences. To that purpose, we used various connexin-targeting peptides interacting with extracellular (Gap26) and intracellular (Gap19, RRNYRRNY) Cx43 domains, and tested their effect on mitochondrial dye- and Ca2+-uptake, electrophysiological properties of plasmalemmal and mitochondrial Cx43 channels, and cell injury/cell death. Our results in isolated mice cardiac subsarcolemmal mitochondria indicate that Cx43 forms hemichannels that contribute to Ca2+ entry and may trigger permeability transition and cell injury/death. RRNYRRNY displayed the strongest effects in all assays and inhibited plasma membrane as well as mitochondrial Cx43 hemichannels. RRNYRRNY also strongly reduced the infarct size in ex vivo cardiac ischemia–reperfusion studies. These results indicate that Cx43 contributes to mitochondrial Ca2+ homeostasis and is involved in triggering cell injury/death pathways that can be inhibited by RRNYRRNY peptide.

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Acknowledgements

This work was supported by the Fund for Scientific Research Flanders, Belgium (G.0A82.13N to L.L. and A.K.G.), the Interuniversity Attraction Poles Program (P7/10 to L.L.), and Ghent University (BOF to L.L.). We are very grateful to Prof. R. Lefebvre for the shared use of equipment. We sincerely thank Dr. Ellen Cocquyt and Thi Thu Hang Dang for superb technical support.

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Authors and Affiliations

  1. Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185 (Block B, Rm 031), 9000, Ghent, Belgium

    Ashish Kumar Gadicherla, Nan Wang, Alessio Lissoni, Maarten De Smet & Luc Leybaert

  2. Physiologisches Institut, Justus-Liebig-Univiersität Giessen, Giessen, Germany

    Marco Bulic, Klaus-Dieter Schlüter & Rainer Schulz

  3. The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA

    Esperanza Agullo-Pascual & Mario Delmar

  4. Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Louvain, Belgium

    Geert Bultynck

  5. Inflammation Research Center, VIB, Ghent, Belgium

    Dmitri V. Krysko

  6. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Dmitri V. Krysko

  7. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Amadou Camara & Wai-Meng Kwok

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  1. Ashish Kumar Gadicherla
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Correspondence to Luc Leybaert.

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Gadicherla, A.K., Wang, N., Bulic, M. et al. Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart. Basic Res Cardiol 112, 27 (2017). https://doi.org/10.1007/s00395-017-0618-1

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