Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease

Figures

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  Fig. 1. Myocardial energy metabolism in diabetic heart disease. The heart in diabetes (both type 1 and type 2) experiences several perturbations in intermediary energy metabolism. In particular, the heart in an individual with diabetes produces the majority of its energy (ATP) from the mitochondrial oxidation of fatty acids (right half of the figure), which comes at the expense of a severe impairment in the mitochondrial oxidation of carbohydrates (i.e., glucose) (left half of the figure). This figure was created with BioRender.com.

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  Fig. 2. Post-translational modifications impacting PDH activity. PDH activity is subject to numerous post-translational modifications, including phosphorylation, which is the best characterized. PDHK mediated phosphorylation inhibits PDH activity, whereas PDHP mediated dephosphorylation stimulates PDH activity. PDH may also be inactivated by acetylation, with recent studies suggesting that increases in mitochondrial acetyl CoA increase mitochondrial protein acetylation nonenzymatically, whereas Sirt3 has been demonstrated to increase PDH activity via deacetylation. Finally, PDH is also subject to S-glutathionylation mediated inactivation, though the role of GST and GRX in catalyzing and removing S-glutathionylation modifications of PDH, respectively, remains to be determined. PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; PDHP, pyruvate dehydrogenase phosphatase; CoA, coenzyme A; Sirt, sirtuin; GST, glutathione-S-transferases; GRX, glutaredoxins.