Cardiac metabolic effects of K1.2 channel deletion and evidence for its mitochondrial localization.

Controversy surrounds the molecular identity of mitochondrial K channels that are important for protection against cardiac ischemia-reperfusion injury. Although K1.2 (sodium-activated potassium channel encoded by Kcn2) is necessary for cardioprotection by volatile anesthetics, electrophysiological evidence for a channel of this type in mitochondria is lacking. The endogenous physiological role of a potential mito-K1.2 channel is also unclear. In this study, single channel patch-clamp of 27 independent cardiac mitochondrial inner membrane (mitoplast) preparations from wild-type (WT) mice yielded 6 channels matching the known ion sensitivity, ion selectivity, pharmacology, and conductance properties of K1.2 (slope conductance, 138 ± 1 pS). However, similar experiments on 40 preparations from Kcnt2 mice yielded no such channels. The K 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 also had elevated body fat, but no baseline differences in the cardiac metabolome. These data support the existence of a cardiac mitochondrial K1.2 channel, and a role for cardiac K1.2 in regulating metabolism under conditions of high energetic demand.-Smith, C. O., Wang, Y. T., Nadtochiy, S. M., Miller, J. H., Jonas, E. A., Dirksen, R. T., Nehrke, K., Brookes, P. S. Cardiac metabolic effects of K1.2 channel deletion and evidence for its mitochondrial localization.