Diazoxide Needs Mitochondrial Connexin43 to Exert Its Cytoprotective Effect in a Cellular Model of CoCl(2)-Induced Hypoxia

Hypoxia is the leading cause of death in cardiomyocytes. Cells respond to oxygen deprivation by activating cytoprotective programs, such as mitochondrial connexin43 (mCx43) overexpression and the opening of mitochondrial K(ATP) channels, aimed to reduce mitochondrial dysfunction. In this study we used an in vitro model of CoCl(2)-induced hypoxia to demonstrate that mCx43 and K(ATP) channels cooperate to induce cytoprotection. CoCl(2) administration induces apoptosis in H9c2 cells by increasing mitochondrial ROS production, intracellular and mitochondrial calcium overload and by inducing mitochondrial membrane depolarization. Diazoxide, an opener of K(ATP) channels, reduces all these deleterious effects of CoCl(2) only in the presence of mCx43. In fact, our results demonstrate that in the presence of radicicol, an inhibitor of Cx43 translocation to mitochondria, the cytoprotective effects of diazoxide disappear. In conclusion, these data confirm that there exists a close functional link between mCx43 and K(ATP) channels.