Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2023-10-11 DOI:10.1007/s00395-023-01015-z
Wenwen Li, Li Quan, Kun Peng, Yanru Wang, Xianhua Wang, Quan Chen, Heping Cheng, Qi Ma
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Abstract

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.

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琥珀酸脱氢酶对心脏的表观遗传学和代谢稳态至关重要。
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。在此,我们发现琥珀酸脱氢酶(SDH)是维持FAO/糖酵解心肌稳态所必需的。心肌细胞限制性缺失SDH亚单位b或c的小鼠发展为扩张型心肌病和心力衰竭。FAO显示,肥大的心脏减少,而葡萄糖摄取和糖酵解增加,通过高脂肪饮食强化FAO燃料来逆转这一趋势,这也改善了突变小鼠的心力衰竭。SDH缺陷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去甲基化酶的代谢产物,导致心肌转录组景观的变化。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-酮戊二酸对琥珀酸盐的抑制恢复了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。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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