Alterations in mitochondrial function contribute to diabetic cardiomyopathy. We have previously shown that heart mitochondrial proteins are hyper-acetylated in OVE26 mice, a transgenic model of type 1 diabetes. However, the universality of this modification and its functional consequences are not well established. In this study, we demonstrate that Akita type 1 diabetic mice exhibit hyper-acetylation. Functionally, isolated Akita heart mitochondria have significantly impaired maximal (state 3) respiration with physiological pyruvate (0.1 mM) but not with 1.0 mM pyruvate. In contrast, pyruvate dehydrogenase activity is significantly decreased regardless of the pyruvate concentration. We found there is a 70% decrease in the rate of pyruvate transport in Akita heart mitochondria, but no decrease in the mitochondrial pyruvate carrier proteins (MPC1 and MPC2). The potential role of hyper-acetylation in mediating this impaired pyruvate uptake was examined. The treatment of control mitochondria with the acetylating agent, acetic anhydride, inhibits pyruvate uptake and pyruvate supported respiration in a similar manner to the pyruvate transport inhibitor α-cyano-4-hydroxycinnamate (CHC). A mass spec selective reactive monitoring assay was developed and used to determine that acetylation of lysines 19 and 26 of MPC2 are enhanced in Akita heart mitochondria. Expression of a double acetylation mimic of MPC2 (K19Q/K26Q) in H9c2 cells was sufficient to decrease the maximal cellular oxygen consumption rate. This study supports the conclusion that deficient pyruvate transport activity, mediated in part by acetylation of MPC2, is a contributor to metabolic inflexibility in the diabetic heart.
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