Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cardiovascular Center, Children's Hospital of Fudan University, Shanghai, China.
Nat Commun. 2024 Nov 16;15(1):9945. doi: 10.1038/s41467-024-54407-7.
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.
Notch 信号激活驱动内皮-间充质转化（EndMT）对于心脏发育至关重要，尽管有证据表明内皮细胞代谢的重编程可以独立于经典细胞信号调节内皮功能。在此，我们研究了 Notch 信号和代谢重编程在 EndMT 过程中的相互作用。生物化学分析发现，NOTCH1 细胞内结构域（NICD1）定位于内皮细胞线粒体，在那里它与复合体相互作用并激活复合体以增强线粒体代谢。与野生型 NICD1 相比，将 NICD1 靶向线粒体可诱导更多的 EndMT，并且在先天性心脏缺陷的小鼠模型中，PDH 的小分子激活在妊娠期间改善表型。在非综合征性法洛四联症患者中观察到的 NOTCH1 突变可减少心脏组织中 NICD1 的线粒体定位和随后的 PDH 活性。总之，我们的研究结果表明 NICD1 在发育中的小鼠心脏的线粒体中富集，通过激活 PDH 诱导 EndMT，随后改善线粒体代谢。
