Abstract
Controversy surrounds the molecular identity of mitochondrial K+ channels important for protection against cardiac ischemia-reperfusion injury. While KNa1.2 (Kcnt2 gene) is necessary for cardioprotection by volatile anesthetics, electrophysiologic evidence for a mitochondrial KNa1.2 is lacking. The endogenous physiologic role of a potential mito-KNa1.2 is also unclear. Herein, single channel patch-clamp of cardiac mitochondrial inner membranes from wild type (WT) and Kcnt2-/- mice yielded respectively 6/27 and 0/40 channels, matching the known ion-sensitivity, ion-selectivity, pharmacology and conductance properties of KNa 1.2 (WT slope conductance 138±1 pS). The KNa opener bithionol uncoupled respiration in WT but not Kcnt2-/- cardiomyocytes. Furthermore, when oxidizing only fat as substrate, Kcnt2-/- cardiomyocytes and hearts were less responsive to increases in energetic demand. Kcnt2-/- mice had elevated body fat, but no baseline differences in the cardiac metabolome. These data support the existence of a cardiac mitochondrial KNa 1.2 channel with a potential metabolic regulatory role under high energetic demand.