Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.
State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
Basic Res Cardiol. 2023 Oct 11;118(1):45. doi: 10.1007/s00395-023-01015-z.
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）向糖酵解的转变。在这里，我们表明琥珀酸脱氢酶（SDH）对于维持心肌 FAO/糖酵解的稳态是必需的。心肌细胞特异性缺失 SDH 亚基 b 或 c 的小鼠会发展为扩张型心肌病和心力衰竭。肥大的心脏表现出 FAO 的减少，而葡萄糖摄取和糖酵解增加，通过高脂肪饮食强制提供 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 缺陷型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 去甲基化酶的代谢物，导致心肌转录组景观发生变化。琥珀酸诱导 DNA 超甲基化并抑制心肌中 FAO 基因的表达，导致 FAO/糖酵解失衡。α-酮戊二酸抑制琥珀酸可恢复 SDH 缺陷型心肌细胞的转录谱和代谢紊乱。因此，我们的发现揭示了 SDH 在衰竭心脏代谢重编程中的重要作用，并强调了在 SDH 缺乏的情况下，治疗策略预防心脏功能障碍的潜力。
