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NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice

Author

Listed:
  • Jie Wang

    (Shanghai Jiao Tong University School of Medicine
    Children’s Hospital of Fudan University
    Children’s Hospital of Fudan University)

  • Rui Zhao

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Sha Xu

    (Sun Yat-sen University Cancer Center)

  • Xiang-Yu Zhou

    (Fudan University)

  • Ke Cai

    (Shanghai Jiao Tong University School of Medicine)

  • Yu-Ling Chen

    (Shanghai Jiao Tong University School of Medicine)

  • Ze-Yu Zhou

    (Shanghai Jiao Tong University School of Medicine)

  • Xin Sun

    (Shanghai Jiao Tong University School of Medicine)

  • Yan Shi

    (Shanghai Jiao Tong University School of Medicine)

  • Feng Wang

    (Children’s Hospital of Fudan University
    Children’s Hospital of Fudan University)

  • Yong-Hao Gui

    (Children’s Hospital of Fudan University
    Children’s Hospital of Fudan University)

  • Hui Tao

    (Anhui Medical University)

  • Jian-Yuan Zhao

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    International Human Phenome Institutes (Shanghai))

Abstract

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism.

Suggested Citation

  • Jie Wang & Rui Zhao & Sha Xu & Xiang-Yu Zhou & Ke Cai & Yu-Ling Chen & Ze-Yu Zhou & Xin Sun & Yan Shi & Feng Wang & Yong-Hao Gui & Hui Tao & Jian-Yuan Zhao, 2024. "NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54407-7
    DOI: 10.1038/s41467-024-54407-7
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    References listed on IDEAS

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    2. Silvia Fre & Mathilde Huyghe & Philippos Mourikis & Sylvie Robine & Daniel Louvard & Spyros Artavanis-Tsakonas, 2005. "Notch signals control the fate of immature progenitor cells in the intestine," Nature, Nature, vol. 435(7044), pages 964-968, June.
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