NAT10 regulates heart development and function by maintaining the expression of genes related to fatty acid β-oxidation and heart contraction

IF 15.4 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation Pub Date : 2025-09-13 DOI:10.1038/s41418-025-01577-6

Lei Shi, Meiwei Zhang, Hao Yang, Xinzhi Li, Siyi He, Yanshuo Chu, Minghui Gao, Zhiguo Zhang, Joe Z. Zhang, Zhuo Li, Zheng Chen

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Abstract

Energy metabolism is crucial for heart development and function, and dysregulation of this process can lead to heart failure. However, the molecular mechanisms underlying these processes, particularly the role of RNA-binding proteins (RBPs)-mediated posttranscriptional regulation, remain largely unclear. We identified N-acetyltransferase 10 (NAT10) as a key regulator of heart function and cardiac diseases. NAT10 is crucial for heart development, and its dysregulation is associated with heart failure. Cardiac-specific deletion of Nat10 leads to dilated cardiomyopathy, heart failure, and postnatal death by downregulating genes related to fatty acid β-oxidation and heart contraction. Adult-onset knockout Nat10 also results in dilated cardiomyopathy and heart failure. NAT10-deficient hiPSC-CMs also showed impaired calcium transients during contraction. Restoration of NAT10(WT) and NAT10(G641E) (an N-acetyltransferase-inactive mutation), but not NAT10(K290A) (a loss-of-RNA-binding activity mutation), fully rescues the dilated cardiomyopathy, heart failure, and postnatal death phenotypes in Nat10-CKO mice by restoring expression of genes involved in fatty acid β-oxidation and heart contraction. The RNA-binding activity of NAT10 is essential for maintaining the expression of these genes. These findings demonstrate that NAT10 plays a critical role in heart development and function by maintaining the expression of genes related to fatty acid β-oxidation and heart contraction, highlighting its importance in maintaining heart health.

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NAT10通过维持脂肪酸β-氧化和心脏收缩相关基因的表达来调节心脏发育和功能

能量代谢对心脏发育和功能至关重要，这一过程的失调会导致心力衰竭。然而，这些过程的分子机制，特别是rna结合蛋白（rbp）介导的转录后调控的作用，在很大程度上仍然不清楚。我们发现n -乙酰转移酶10 （NAT10）是心脏功能和心脏疾病的关键调节因子。NAT10对心脏发育至关重要，其失调与心力衰竭有关。心脏特异性缺失Nat10通过下调脂肪酸β-氧化和心脏收缩相关基因导致扩张性心肌病、心力衰竭和产后死亡。成人发病的Nat10基因敲除也会导致扩张性心肌病和心力衰竭。缺乏nat10的hiPSC-CMs在收缩期间也表现出钙瞬态受损。恢复NAT10（WT）和NAT10(G641E)（一种n -乙酰转移酶失活突变），而不是NAT10(K290A)（一种rna结合活性缺失突变），通过恢复脂肪酸β氧化和心脏收缩相关基因的表达，完全挽救了NAT10 - cko小鼠的扩张型心肌病、心力衰竭和出生后死亡表型。NAT10的rna结合活性对于维持这些基因的表达至关重要。这些发现表明，NAT10通过维持脂肪酸β-氧化和心脏收缩相关基因的表达，在心脏发育和功能中起着关键作用，突出了其在维持心脏健康中的重要性。

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来源期刊

Cell Death and Differentiation 生物-生化与分子生物学

CiteScore

24.70

自引率

1.60%

发文量

181

审稿时长

3 months

期刊介绍： Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.