Slo2.x Potassium Channels are Involved in the Regulation of Heart Mitochondrial Function

Abstract

Mitochondrial potassium channels (MKCs) are believed to be important in stress response in the heart. Volatile anesthetic preconditioning (APC) is a method of protecting the heart from ischemia-reperfusion injury which elicits evolutionarily-conserved protective signaling pathways that converge at the mitochondrial level. Work in C. elegans has focused attention on the Slo2 gene product as a transducer of APC effects on hypoxic survival and recent data from our lab demonstrate that this protective role is conserved in mammals. Slo2 in mammals has diverged into two paralogs, Slo2.1 (KCNT2; Slick) and Slo2.2 (KCNT1; Slack). These genes code for Na+-activated K+ channels and are highly expressed in brain, but their function in cardiomyocytes and/or mitochondria is unknown. Examination of these channels has been limited to pharmacologic profiling which is hampered by overlapping sensitivities and off-target effects of small molecules. Herein we employed novel genetic deletions of Slo2.1 and Slo2.2 double knockout, Slo2.x dKO, in mice to confirm the role of these potassium channels in APC and identify their role in endogenous cardiac mitochondrial function. Preliminary data obtained using Slo2.x dKO reveal novel metabolic and morphologic phenotypes, indicating a functional relationship between mitochondrial potassium channels and regulation of mitochondrial oxidative phosphorylation. These data demonstrate a role of the Slo2.x gene product in the regulation of cardiac mitochondrial function.