A hallmark of heart failure is a metabolic switch away from fatty acids β-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 α-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.

心力衰竭的一个标志是代谢从脂肪酸 β-氧化 (FAO) 转变为糖酵解。在这里，我们表明琥珀酸脱氢酶（SDH）是维持心肌脂肪酸/糖酵解稳态所必需的。心肌细胞限制性删除 SDH b 或 c 亚基的小鼠会出现扩张型心肌病和心力衰竭。肥大的心脏表现出FAO减少，而葡萄糖摄取和糖酵解增加，通过高脂肪饮食强制FAO燃料可以逆转这种情况，这也改善了突变小鼠的心力衰竭。 SDH 缺陷的心脏表现出与琥珀酸积累相关的全基因组 DNA 甲基化增加，琥珀酸是一种已知抑制 DNA 去甲基酶的代谢物，导致心肌转录组景观的变化。琥珀酸诱导DNA高甲基化并抑制心肌中FAO基因的表达，导致FAO/糖酵解失衡。 α-酮戊二酸对琥珀酸的抑制可恢复 SDH 缺陷心肌细胞的转录谱和代谢紊乱。因此，我们的研究结果揭示了 SDH 在衰竭心脏代谢重塑中的重要作用，并强调了在 SDH 缺乏的情况下预防心脏功能障碍的治疗策略的潜力。