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

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 () and Jian-Yuan Zhao ()
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Jie Wang: Shanghai Jiao Tong University School of Medicine
Rui Zhao: 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
Yong-Hao Gui: Children’s Hospital of Fudan University
Hui Tao: Anhui Medical University
Jian-Yuan Zhao: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54407-7

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