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Background Inhibitors of the sodium‐glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium‐glucose linked transporter 2 inhibition on mitochondrial function, high‐energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet‐induced diabetic cardiomyopathy. Methods and Results Mice fed a control diet or a high‐fat, high‐sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High‐energy phosphates were assessed by 31 P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high‐fat, high‐sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet. Conclusions Ertugliflozin not only prevented high‐fat, high‐sucrose–induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium‐glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.

Background Mitochondrial reactive oxygen species ( ROS ) are associated with metabolic heart disease ( MHD ). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD . Methods and Results Mice fed a high‐fat high‐sucrose ( HFHS ) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild‐type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS ‐fed wild‐type mice had a 3‐fold greater rate of H 2 O 2 production ( P =0.001 versus control diet fed), a 30% decrease in complex II substrate–driven oxygen consumption ( P =0.006), 21% to 23% decreases in complex I and II substrate–driven ATP synthesis ( P =0.01), and a 62% decrease in complex II activity ( P =0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet–induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS ‐fed wild‐type mice complex II substrate–driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site‐directed mutation of complex II subunit B Cys100 or Cys103 to redox‐insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium. Conclusion Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103.