Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts
Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts
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DOI：
10.1007/s00395-023-01015-z
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发表时间：
2023-10
影响因子：
9.5
通讯作者：
Wenwen Li;Li Quan;Kun Peng;Yanru Wang;Xianhua Wang;Quan Chen;Heping Cheng;Qi Ma
中科院分区：
文献类型：
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作者：
Wenwen Li;Li Quan;Kun Peng;Yanru Wang;Xianhua Wang;Quan Chen;Heping Cheng;Qi Ma
心力衰竭的标志是从脂肪酸β-氧化（FAO）到糖酵解的代谢转换。在这里，我们表明，琥珀酸脱氢酶（SDH）是必需的FAO/糖酵解的心肌稳态的维持。SDH亚基B或c心肌细胞限制性缺失的小鼠发生扩张型心肌病和心力衰竭。肥大的心脏显示FAO减少，而葡萄糖摄取和糖酵解增加，这通过通过高脂肪饮食强制FAO燃料来逆转，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甲基化的增加，琥珀酸是一种已知抑制DNA去甲基化酶的代谢物，导致心肌转录组景观的变化。琥珀酸可诱导心肌细胞DNA甲基化，抑制FAO基因表达，导致FAO/糖酵解失衡。α-酮戊二酸对琥珀酸的抑制恢复了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在衰竭心脏的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功能障碍的治疗策略的潜力。
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.