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NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the
Jie Wang1,2,3, Rui Zhao1,4, Sha Xu5
1Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
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