%0 Journal Article %A Charles O. Smith %A Yves T. Wang %A Sergiy M Nadtochiy %A James H. Miller %A Elizabeth A. Jonas %A Robert T. Dirksen %A Keith Nehrke %A Paul S. Brookes %T Cardiac metabolic effects of KNa1.2 channel deletion, and evidence for its mitochondrial localization %D 2018 %R 10.1101/223321 %J bioRxiv %P 223321 %X Controversy surrounds the molecular identity of mitochondrial K+ channels that are important for protection against cardiac ischemia-reperfusion injury. While KNa1.2 (Kcnt2 gene) is necessary for cardioprotection by volatile anesthetics, electrophysiologic evidence for a channel of this type in mitochondria is lacking. The endogenous physiologic role of a potential mito-KNa1.2 channel is also unclear. Herein, 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 KNa1.2 (slope conductance 138±1 pS). However, similar experiments on 40 preparations from Kcnt2-/- mice yielded zero such channels. 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 also had elevated body fat, but no baseline differences in the cardiac metabolome. These data support the existence of a cardiac mitochondrial KNa1.2 channel, and a role for cardiac KNa1.2 in regulating metabolism under conditions of high energetic demand.Non-standard abbreviationsIR injuryIschemia-Reperfusion injuryIPCIschemic PreconditioningAPCAnesthetic PreconditioningKNaSodium activated potassium channelKNa1.1(channel encoded by Kcnt1 (formerly Slo2.2)), aka Slack, KCa4.1, SLO2.2KNa1.2(channel encoded by Kcnt2 (formerly Slo2.1)), aka Slick, KCa4.2, SLO2.1BTBithionol, aka Bis(2-hydroxy-3,5-dichlorophenyl)SulfideOCROxygen consumption rateROSReactive oxygen species %U https://www.biorxiv.org/content/biorxiv/early/2018/01/23/223321.full.pdf