title: Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart.
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.
authors.affiliation: 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.
authors.forename: Ashish Kumar
authors.initials: AK
authors.lastname: Gadicherla
authors.affiliation: 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.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Physiologisches Institut, Justus-Liebig-Univiersität Giessen, Giessen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Bulic
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Agullo-Pascual
authors.affiliation: 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.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lissoni
authors.affiliation: 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.
authors.forename: Maarten
authors.initials: M
authors.lastname: De Smet
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
authors.affiliation: Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Louvain, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Krysko
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Amadou
authors.initials: A
authors.lastname: Camara
authors.affiliation: Physiologisches Institut, Justus-Liebig-Univiersität Giessen, Giessen, Germany.
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Schlüter
authors.affiliation: Physiologisches Institut, Justus-Liebig-Univiersität Giessen, Giessen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Wai-Meng
authors.initials: WM
authors.lastname: Kwok
authors.affiliation: 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. Luc.Leybaert@UGent.be.
authors.forename: Luc
authors.identifier: 0000-0001-6452-6982
authors.initials: L
authors.lastname: Leybaert
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D018031:Connexin 43 / Q000378:metabolism*; D000067268:Isolated Heart Preparation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D018408:Patch-Clamp Techniques
chemical_list: D018031:Connexin 43; D002118:Calcium
keywords: Calcium; Connexin 43; Ischemia; Mitochondria; Peptidomimetics