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Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts

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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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Data are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Wei Xu for mass spectrometry analysis; Dr. Yuli Liu for echocardiography; Dr. Lin Pan and Dr. Dongwei Ma for histology; Dr. Chuanyun Li and Dr. Jiguang Peng for bioinformatics analysis; Dr. Aibin He, Dr. Ruiping Xiao, and Dr. Yan Zhang for comments. This work was supported by the National Key Basic Research Program of China (2017YFA0504000 and 2016YFA0500403) and the National Science Foundation of China (32293211, 8182780030, 31821091 and 31971158).

Funding

National Key Basic Research Program of China, 2017YFA0504000, Heping Cheng, 2016YFA0500403, Heping Cheng, the National Science Foundation of China, 31770201, Heping Cheng, 31821091, Heping Cheng, 31971158, Heping Cheng, he National Science Foundation of China, 8182780030, Heping Cheng

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Authors and Affiliations

  1. Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China

    Wenwen Li

  2. 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

    Li Quan, Kun Peng, Yanru Wang, Xianhua Wang, Heping Cheng & Qi Ma

  3. Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China

    Xianhua Wang & Heping Cheng

  4. College of Life Sciences, Nankai University, Tianjin, China

    Quan Chen

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  1. Wenwen Li
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Li, W., Quan, L., Peng, K. et al. Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts. Basic Res Cardiol 118, 45 (2023). https://doi.org/10.1007/s00395-023-01015-z

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