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) and altered glucose metabolism. While mitoK 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. We assessed glucose uptake in mice overexpressing SUR2A-55 (TG) 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 mice. TG had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TG mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TG mice but not from WT mice. In addition, TG 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 mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.