Diabetes mellitus reduces the function and expression of ATP-dependent K+ channels in cardiac mitochondria

Aim: Our goal was to determine the effects of type I diabetes mellitus on the function and expression of ATP-dependent K+ channels in cardiac mitochondria (mitoK(ATP)), composed of a pore-forming subunit (Kir6.1) and a diazoxide-sensitive sulphonylurea receptor (SUR1). We tested the hypothesis that diabetes reduces Kir6.1 and SUR1 expression as well as diazoxide-induced depolarization of mitochondrial membrane potential (Delta Psi m). Main methods: Male FVB mice were made diabetic for 5 weeks with multiple low dose injections of streptozotocin. Cardiac mitochondria were separated into two populations: subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). mitoK(ATP) expression was determined via Western blot analysis of Kir6.1 and SUR1 proteins. mitoK(ATP) function was determined by measuring Delta Psi m with the potentiometric dye rhodamine 123. Key findings: Diabetes reduced Kir6.1 and SUR1 expression in IFM by over 40% (p<0.05 for both). Similarly, diabetes reduced Kir6.1 expression in SSM by approximately 40% (p<0.05); however, SUR1 expression was unaffected. Opening mitoK(ATP) with diazoxide (100 mu M) depolarized control IFM Delta Psi m by 80% of the valinomycin maximum; diabetic IFM depolarized only 30% (p<0.05). Diazoxide-induced depolarization was much less in SSM (20-30%) and unaffected by diabetes. Significance: Our data indicate that diabetes reduces mitoK(ATP) expression and function in IFM. These changes in mitoK(ATP) may provide an opportunity to understand mechanisms leading to diabetic cardiomyopathy and loss of cardioprotective mechanisms in the diabetic heart. (c) 2013 Elsevier Inc. All rights reserved.