Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts

A hallmark of heart failure is a metabolic switch away from fatty acids beta-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required for maintenance of myocardial homeostasis of FAO/glycolysis. Mice with cardiomyocyte-restricted deletion of subunit b or c of SDH developed a dilated cardiomyopathy and heart failure. Hypertrophied hearts displayed a decrease in FAO, while glucose uptake and glycolysis were augmented, which was reversed by enforcing FAO fuels via a high-fat diet, which also improved heart failure of mutant mice. SDH-deficient hearts exhibited an increase in genome-wide DNA methylation associated with accumulation of succinate, a metabolite known to inhibit DNA demethylases, resulting in changes of myocardial transcriptomic landscape. Succinate induced DNA hypermethylation and depressed the expression of FAO genes in myocardium, leading to imbalanced FAO/glycolysis. Inhibition of succinate by alpha-ketoglutarate restored transcriptional profiles and metabolic disorders in SDH-deficient cardiomyocytes. Thus, our findings reveal the essential role for SDH in metabolic remodeling of failing hearts, and highlight the potential of therapeutic strategies to prevent cardiac dysfunction in the setting of SDH deficiency.

Automated summary

A metabolic switch from fatty acids beta-oxidation (FAO) to glycolysis is a prominent feature of heart failure. Succinate dehydrogenase (SDH) is found to be essential in maintaining the balance of FAO/glycolysis in myocardium. SDH deficiency leads to dilated cardiomyopathy and heart failure, accompanied by a decrease in FAO and an increase in glycolysis. Enforcing FAO through a high-fat diet can reverse these changes and improve heart failure.