Tang Yuyi, Zhang Jingjing, Fang Yixuan, Zhu Kai, Zhu Jingqiao, Huang Ce, Xie Zhuxin, Zhang Shan, Ma Wenrui, Yan Guoquan, Liu Shaowen, Liu Xin, Han Wenjing, Xin Yue, Yang Chenxi, Abudupataer Mieradilijiang, Zhou Peiyun, He Chenxi, Lai Hao, Wang Chunsheng, Liu Yang, Lan Fei, Ye Dan, Yu Fa-Xing, Xu Yanhui, Zhang Weijia
Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China.
Nat Cardiovasc Res. 2025 Feb;4(2):235-247. doi: 10.1038/s44161-024-00603-z. Epub 2025 Jan 14.
Loss-of-function mutations in NOTCH1 were previously linked to thoracic aortopathy, a condition for which non-surgical treatment options are limited. Based on clinical proteome analysis, we hypothesized that mitochondrial fusion and biogenesis in aortic smooth muscle cells (SMCs) are crucial for regulating the progression of NOTCH1-related aortopathy. Here we demonstrate that SMC-specific Notch1 knockout mice develop aortic pathology, including stiffening, dilation and focal dissection. These changes are accompanied by decreased expression of MFN1/2 and TFAM, mirroring findings in human patients. SMC-specific deletion of Mfn1 and/or Mfn2 genes recapitulates the aortopathy seen in Notch1-deficient mice. Prophylactic or therapeutic approaches aimed at increasing mitochondrial DNA copy number, either through AAV-mediated overexpression of Mfn1/2 or oral treatment with mitofusion activators teriflunomide or leflunomide, help mitigate or slow the progression of aortopathy in SMC-Notch1 mice. Our findings provide a molecular framework for exploring pharmacological interventions to restore mitochondrial function in NOTCH1-related aortopathy.
NOTCH1功能丧失突变先前与胸主动脉病变有关，而这种疾病的非手术治疗选择有限。基于临床蛋白质组分析，我们推测主动脉平滑肌细胞（SMC）中的线粒体融合和生物发生对于调节NOTCH1相关主动脉病变的进展至关重要。在此，我们证明平滑肌细胞特异性Notch1基因敲除小鼠会出现主动脉病变，包括僵硬、扩张和局灶性夹层。这些变化伴随着MFN1/2和TFAM表达的降低，这与人类患者的研究结果一致。平滑肌细胞特异性缺失Mfn1和/或Mfn2基因可重现Notch1缺陷小鼠中出现的主动脉病变。通过腺相关病毒介导的Mfn1/2过表达或用线粒体融合激活剂来氟米特或特立氟胺进行口服治疗，旨在增加线粒体DNA拷贝数的预防或治疗方法有助于减轻或减缓SMC-Notch1小鼠主动脉病变的进展。我们的研究结果为探索药物干预以恢复NOTCH1相关主动脉病变中的线粒体功能提供了分子框架。
