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

作者：Gadicherla Ashish Kumar; Wang Nan; Bulic Marco; Agullo Pascual Esperanza; Lissoni Alessio; De Smet Maarten; Delmar Mario; Bultynck Geert; Krysko Dmitri V; Camara Amadou; Schlueter Klaus Dieter; Schulz Rainer; Kwok Wai Meng; Leybaert Luc^*

来源：Basic Research in Cardiology, 2017, 112(3): 27.

DOI：10.1007/s00395-017-0618-1

• Mitochondria
• Connexin 43
• Ischemia
• Calcium
• Peptidomimetics

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.

• 出版日期2017-5