Doxorubicin-Mediated Cardiotoxicity: Role of Mitochondrial Connexin 43

Doxorubicin is the highly effective anthracycline, but its clinical use is limited by cardiotoxicity and consequent dysfunction. It has been proposed that the etiology of this is related to mitochondrial dysfunction. Connexin 43 (Cx43), the principal protein building block of cardiac gap junctions and hemichannels, plays an important role in cardioprotection. Recent reports confirmed the presence of Cx43 in the mitochondria as well. In this study, the role of mitochondrial Cx43 was evaluated 3 or 6 h after Doxorubicin administration to the rat heart cell line H9c2. Pharmacological inhibition of Hsp90 demonstrated that the mitochondrial Cx43 conferred cardioprotection by reducing cytosolic and mitochondrial reactive oxygen species production, mitochondrial calcium overload and mitochondrial membrane depolarization and cytochrome c release. In conclusion, our study demonstrates that Cx43 plays an important role in the protection of cardiac cells from Doxorubicin-induced toxicity.