Cardiac metabolic effects of KNa1.2 channel deletion and evidence for its mitochondrial localization

Abstract

<p class="first" id="d110621e238">Controversy surrounds the molecular identity of mitochondrial K ⁺ channels that are important for protection against cardiac ischemia–reperfusion injury. Although K _Na1.2 (sodium-activated potassium channel encoded by <i>Kcn2</i>) 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-K _Na1.2 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 K _Na1.2 (slope conductance, 138 ± 1 pS). However, similar experiments on 40 preparations from <i>Kcnt2</i> ^−/− mice yielded no such channels. The K _Na opener bithionol uncoupled respiration in WT but not <i>Kcnt2</i> ^−/− cardiomyocytes. Furthermore, when oxidizing only fat as substrate, <i>Kcnt2</i> ^−/− cardiomyocytes and hearts were less responsive to increases in energetic demand. <i>Kcnt2</i> ^−/− mice also had elevated body fat, but no baseline differences in the cardiac metabolome. These data support the existence of a cardiac mitochondrial K _Na1.2 channel, and a role for cardiac K _Na1.2 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 K _Na1.2 channel deletion and evidence for its mitochondrial localization. </p>