Overexpression of a Short Sulfonylurea Splice Variant Increases Cardiac Glucose Uptake and Uncouples Mitochondria by Regulating ROMK Activity

The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased mitochondrial ATP sensitive K(+) channel activity (mitoK(ATP)) and altered glucose metabolism. While mitoK(ATP) channels composed of CCDC51 and ABCB8 exist, the mitochondrial K(+) pore regulated by SUR2A-55 is unknown. We explored whether SUR2A-55 regulates ROMK to form an alternate mitoK(ATP). We assessed glucose uptake in mice overexpressing SUR2A-55 (TG(SUR2A−55)) compared with WT mice during IR injury. We then examined the expression level of ROMK and the effect of ROMK modulation on mitochondrial membrane potential (Δψm) in WT and TG(SUR2A−55) mice. TG(SUR2A−55) had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TG(SUR2A−55) mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TG(SUR2A−55) mice but not from WT mice. In addition, TG(SUR2A−55) and ROMK inhibitor treated WT isolated cardiomyocytes had enhanced mitochondrial uncoupling. ROMK inhibition blocked diazoxide induced Δψm depolarization and prevented preservation of Δψm from FCCP perfusion in WT and to a lesser degree TG(SUR2A−55) mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.