Correcting mitochondrial loss mitigates NOTCH1-related aortopathy in mice

Yuyi Tang; Jingjing Zhang; Yixuan Fang; Kai Zhu; Jingqiao Zhu; Ce Huang; Zhuxin Xie; Shan Zhang; Wenrui Ma; Guoquan Yan; Shaowen Liu; Xin Liu; Wenjing Han; Yue Xin; Chenxi Yang; Mieradilijiang Abudupataer; Peiyun Zhou; Chenxi He; Hao Lai; Chunsheng Wang; Yang Liu; Fei Lan; Dan Ye; Fa-Xing Yu; Yanhui Xu; Weijia Zhang

doi:10.1038/s44161-024-00603-z

Correcting mitochondrial loss mitigates NOTCH1-related aortopathy in mice

Nat Cardiovasc Res. 2025 Jan 14. doi: 10.1038/s44161-024-00603-z. Online ahead of print.

Authors

Yuyi Tang^#¹, Jingjing Zhang^#^{1

2

3}, Yixuan Fang^#¹, Kai Zhu^#⁴, Jingqiao Zhu¹, Ce Huang³, Zhuxin Xie¹, Shan Zhang¹, Wenrui Ma⁴, Guoquan Yan¹, Shaowen Liu¹, Xin Liu¹, Wenjing Han¹, Yue Xin¹, Chenxi Yang¹, Mieradilijiang Abudupataer⁴, Peiyun Zhou¹, Chenxi He¹, Hao Lai⁴, Chunsheng Wang⁴, Yang Liu⁵, Fei Lan¹, Dan Ye¹, Fa-Xing Yu¹, Yanhui Xu¹, Weijia Zhang^{6

7

8}

Affiliations

¹ Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
² State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China.
³ Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁶ Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. weijiazhang@fudan.edu.cn.
⁷ State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China. weijiazhang@fudan.edu.cn.
⁸ Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China. weijiazhang@fudan.edu.cn.

^# Contributed equally.

PMID: 39809927
DOI: 10.1038/s44161-024-00603-z

Abstract

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.

Abstract

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