Effect of Dl-3-n-butylphthalide on mitochondrial Cox7c in models of cerebral ischemia/reperfusion injury

Jingjing Jia; Jianwen Deng; Haiqiang Jin; Jie Yang; Ding Nan; Zemou Yu; Weiwei Yu; Zhiyuan Shen; Yuxuan Lu; Ran Liu; Zhaoxia Wang; Xiaozhong Qu; Dong Qiu; Zhenzhong Yang; Yining Huang

doi:10.3389/fphar.2023.1084564

Effect of Dl-3-n-butylphthalide on mitochondrial Cox7c in models of cerebral ischemia/reperfusion injury

Front Pharmacol. 2023 Feb 22:14:1084564. doi: 10.3389/fphar.2023.1084564. eCollection 2023.

Authors

Jingjing Jia^{1

2}, Jianwen Deng¹, Haiqiang Jin¹, Jie Yang³, Ding Nan^{1

4}, Zemou Yu^{1

2}, Weiwei Yu^{1

5}, Zhiyuan Shen¹, Yuxuan Lu¹, Ran Liu¹, Zhaoxia Wang¹, Xiaozhong Qu⁶, Dong Qiu⁷, Zhenzhong Yang⁸, Yining Huang¹

Affiliations

¹ Department of Neurology, Peking University First Hospital, Beijing, China.
² National Center for Children's Health, Department of Neurology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
³ Leewe Biopharmaceutical Co., Ltd, Xianlin University, Nanjing, China.
⁴ Department of Hyperbaric Oxygen, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
⁵ Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
⁶ Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing, China.
⁷ Beijing National Laboratory for Molecular Sciences (BNLMS), Laboratory of Polymer Physics and Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
⁸ Institute of Polymer Science and Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, China.

Abstract

Several studies have demonstrated the protective effect of dl-3-n-Butylphthalide (NBP) against cerebral ischemia, which may be related to the attenuation of mitochondrial dysfunction. However, the specific mechanism and targets of NBP in cerebral ischemia/reperfusion remains unclear. In this study, we used a chemical proteomics approach to search for targets of NBP and identified cytochrome C oxidase 7c (Cox7c) as a key interacting target of NBP. Our findings indicated that NBP inhibits mitochondrial apoptosis and reactive oxygen species (ROS) release and increases ATP production through upregulation of Cox7c. Subsequently, mitochondrial respiratory capacity was improved and the HIF-1α/VEGF pathway was upregulated, which contributed to the maintenance of mitochondrial membrane potential and blood brain barrier integrity and promoting angiogenesis. Therefore, our findings provided a novel insight into the mechanisms underlying the neuroprotective effects of NBP, and also proposed for the first time that Cox7c exerts a critical role by protecting mitochondrial function.

Keywords: Dl-3-n-butylphthalide; ROS; cerebral ischemia/reperfusion; cytochrome c oxidase; mitochondrial dysfunction.

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (General Program 81971115, and 82071306), the Beijing Key Laboratory (BZ0250), and the China International Medical Foundation.