Loss of NAT10 Reduces the Translation of Kmt5a mRNA Through ac4C Modification in Cardiomyocytes and Induces Heart Failure

Ting Xu; Tailai Du; Xiaodong Zhuang; Xin He; Youchen Yan; Jialing Wu; Huimin Zhou; Yan Li; Xinxue Liao; Jiangui He; Chen Liu; Yugang Dong; Jingsong Ou; Shuibin Lin; Demeng Chen; Zhan-Peng Huang

doi:10.1161/JAHA.124.035714

Loss of NAT10 Reduces the Translation of Kmt5a mRNA Through ac4C Modification in Cardiomyocytes and Induces Heart Failure

J Am Heart Assoc. 2024 Oct 11:e035714. doi: 10.1161/JAHA.124.035714. Online ahead of print.

Authors

Ting Xu^{1

2}, Tailai Du^{1

2}, Xiaodong Zhuang^{1

2}, Xin He^{1

2}, Youchen Yan^{1

2}, Jialing Wu^{1

2}, Huimin Zhou^{1

2}, Yan Li^{1

2

3

4}, Xinxue Liao^{1

2}, Jiangui He^{1

2}, Chen Liu^{1

2

4}, Yugang Dong^{1

2}, Jingsong Ou^{1

2

3

4}, Shuibin Lin¹, Demeng Chen¹, Zhan-Peng Huang^{1

2

3

4}

Affiliations

¹ Department of Cardiology, Center for Translational Medicine Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University Guangzhou China.
² NHC Key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University) Guangzhou China.
³ Division of Cardiac Surgery National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital, Sun Yat-sen University Guangzhou China.
⁴ Key Laboratory of Assisted Circulation and Vascular Diseases Chinese Academy of Medical Sciences, The First Affiliated Hospital, Sun Yat-sen University Guangzhou China.

PMID: 39392166
DOI: 10.1161/JAHA.124.035714

Abstract

Background: In the past decade, the biological functions of various RNA modifications in mammals have been uncovered. N4-acetylcytidine (ac4C), a highly conserved RNA modification, has been implicated in human diseases. Despite this, the involvement of RNA ac4C modification in cardiac physiology and pathology remains incompletely understood. NAT10 (N-acetyltransferase 10) stands as the sole acetyltransferase known to catalyze RNA ac4C modification. This study aims to explore the role of NAT10 and ac4C modification in cardiac physiology and pathology.

Methods and results: Cardiac-specific knockout of NAT10, leading to reduced RNA ac4C modification, during both neonatal and adult stages resulted in severe heart failure. NAT10 deficiency induced cardiomyocyte apoptosis, a crucial step in heart failure pathogenesis, supported by in vitro data. Activation of the p53 signaling pathway was closely associated with enhanced apoptosis in NAT10-deficient cardiomyocytes. As ac4C modification on mRNA influences translational efficiency, we employed ribosome footprints coupled with RNA sequencing to explore genome-wide translational efficiency changes caused by NAT10 deficiency. We identified and validated that the translational efficiency of Kmt5a was suppressed in NAT10 knockout hearts due to reduced ac4C modification on its mRNA. This finding was consistent with the observation that Kmt5a protein levels were reduced in heart failure despite unchanged mRNA expression. Knockdown of Kmt5a in cardiomyocytes recapitulated the phenotype of NAT10 deficiency, including increased cardiomyocyte apoptosis and activated p53 signaling. Finally, overexpression of Kmt5a rescued cardiomyocyte apoptosis and p53 activation induced by NAT10 inhibition.

Conclusions: Our study highlights the significance of NAT10 in cardiomyocyte physiology, demonstrating that NAT10 loss is sufficient to induce cardiomyocyte apoptosis and heart failure. NAT10 regulates the translational efficiency of Kmt5a, a key mediator, through mRNA ac4C modification during heart failure.

Keywords: Kmt5a; NAT10; ac4C modification; heart failure; p53 signaling.