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N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration

Author

Listed:
  • Wenya Ma

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University
    Harbin Medical University)

  • Yanan Tian

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Leping Shi

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Jing Liang

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Qimeng Ouyang

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Jianglong Li

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Hongyang Chen

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Hongyue Sun

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Haoyu Ji

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Xu Liu

    (Harbin Medical University
    Harbin Medical University)

  • Wei Huang

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Xinlu Gao

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Xiaoyan Jin

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Xiuxiu Wang

    (Harbin Medical University)

  • Yining Liu

    (Harbin Medical University)

  • Yang Yu

    (Harbin Medical University)

  • Xiaofei Guo

    (Harbin Medical University)

  • Ye Tian

    (Harbin Medical University)

  • Fan Yang

    (Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Faqian Li

    (University of Minnesota)

  • Ning Wang

    (Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University)

  • Benzhi Cai

    (Harbin Medical University
    Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University
    Harbin Medical University)

Abstract

Translational control is crucial for protein production in various biological contexts. Here, we use Ribo-seq and RNA-seq to show that genes related to oxidative phosphorylation are translationally downregulated during heart regeneration. We find that Nat10 regulates the expression of Uqcr11 and Uqcrb mRNAs in mouse and human cardiomyocytes. In mice, overexpression of Nat10 in cardiomyocytes promotes cardiac regeneration and improves cardiac function after injury. Conversely, treating neonatal mice with Remodelin—a Nat10 pharmacological inhibitor—or genetically removing Nat10 from their cardiomyocytes both inhibit heart regeneration. Mechanistically, Nat10 suppresses the expression of Uqcr11 and Uqcrb independently of its ac4C enzyme activity. This suppression weakens mitochondrial respiration and enhances the glycolytic capacity of the cardiomyocytes, leading to metabolic reprogramming. We also observe that the expression of Nat10 is downregulated in the cardiomyocytes of P7 male pig hearts compared to P1 controls. The levels of Nat10 are also lower in female human failing hearts than non-failing hearts. We further identify the specific binding regions of Nat10, and validate the pro-proliferative effects of Nat10 in cardiomyocytes derived from human embryonic stem cells. Our findings indicate that Nat10 is an epigenetic regulator during heart regeneration and could potentially become a clinical target.

Suggested Citation

  • Wenya Ma & Yanan Tian & Leping Shi & Jing Liang & Qimeng Ouyang & Jianglong Li & Hongyang Chen & Hongyue Sun & Haoyu Ji & Xu Liu & Wei Huang & Xinlu Gao & Xiaoyan Jin & Xiuxiu Wang & Yining Liu & Yang, 2024. "N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46458-7
    DOI: 10.1038/s41467-024-46458-7
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