DEAD-box helicase 17(DDX17)protects cardiac function by promoting mitochondrial homeostasis in heart failure

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外文摘要：DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We generated cardiomyocyte-specific Ddx17-knockout mice(Ddx17-cKO),cardiomyocyte-specific Ddx17 transgenic mice(Ddx17-Tg),and various models of cardiomyocyte injury and heart failure(HF).DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury.Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis,leading to progressive cardiac dysfunction,maladaptive remodeling and progression to heart failure.Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions.Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6(BCL6)and inhibit the expression of dynamin-related protein 1(DRP1).When DDX17 expression is reduced,transcriptional repression of BCL6 is attenuated,leading to increased DRP1 expression and mitochondrial fission,which in turn leads to impaired mitochondrial homeostasis and heart failure.We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure.These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.

作者：

Mingjing Yan、Junpeng Gao、Ming Lan、Que Wang、Yuan Cao、Yuxuan Zheng、Yao Yang、Wenlin Li、Xiaoxue Yu、Xiuqing Huang、Lin Dou、Bing Liu、Junmeng Liu、Hongqiang Cheng、Kunfu Ouyang、Kun Xu、Shenghui Sun、Jin Liu、Weiqing Tang、Xiyue Zhang、Yong Man、Liang Sun、Jianping Cai、Qing He、Fuchou Tang、Jian Li、Tao Shen

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作者单位：

The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital/National Center of Gerontology of National Health Commission,Beijing 100730,China

Peking University Fifth School of Clinical Medicine,Beijing 100730,China

Department of Laboratory Medicine,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,China

Biomedical Pioneering Innovation Center,School of Life Sciences,Peking University,Beijing 100871,China

Emergency Center,Zhongnan Hospital of Wuhan University,Wuhan 430071,China

Department of Cardiology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100730,China

Graduate School of Peking Union Medical College,Beijing 100730,China

Department of Health Care,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China

Peking-Tsinghua Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing 100871,China

Department of Pathology and Pathophysiology and Department of Cardiology at Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310058,China

Department of Cardiovascular Surgery,Peking University Shenzhen Hospital,Shenzhen 518036,China

Experimental Technology Center for Life Sciences at Beijing Normal University,Beijing 100875,China

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基金：

National Key R&D Program of ChinaNational Key R&D Program of ChinaChinese Academy of Medical.Sciences(CAMS)Innovation Fund for Medical SciencesChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaBeijing Natural Science FoundationBeijing Natural Science FoundationBeijing Hospital Clinical Research 121 ProjectNational High Level Hospital Clinical Research FundingNational High Level Hospital Clinical Research FundingNational High Level Hospital Clinical Research Funding

项目编号：

2021YFE01142002018YFC20001002021-I2M-1-0502023M732704817702288237058481470427U23A2047072321417212086121-2016004BJ-2021-199BJ-2023-156BJ-2019-159

出版年：

2024

DOI：

10.1038/s41392-024-01831-2

信号转导与靶向治疗(英文)

CSTPCD

ISSN：

年,卷(期)：2024.9(6)