Faculty Collaboration Database

Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart. Basic Res Cardiol 2017 May;112(3):27

Date

04/02/2017

Pubmed ID

28364353

DOI

10.1007/s00395-017-0618-1

Scopus ID

2-s2.0-85016781519 (requires institutional sign-in at Scopus site)   122 Citations

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.

Author List

Gadicherla AK, Wang N, Bulic M, Agullo-Pascual E, Lissoni A, De Smet M, Delmar M, Bultynck G, Krysko DV, Camara A, Schlüter KD, Schulz R, Kwok WM, Leybaert L

Authors

Ashish K. Gadicherla PhD Assistant Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Cell Death
Connexin 43
Isolated Heart Preparation
Male
Mice
Mice, Inbred C57BL
Mitochondria
Myocytes, Cardiac
Patch-Clamp Techniques