2. Academic Validation
  3. A dual-labeling molecule for efficient drug discovery of mitochondrial-lysosomal interactions

A dual-labeling molecule for efficient drug discovery of mitochondrial-lysosomal interactions

  • Mol Cell Probes. 2024 Aug:76:101968. doi: 10.1016/j.mcp.2024.101968.
Jinfang Wu 1,  Xiaolei Wang 2,  Xiang Li 1,  Zixuan Zhu 1,  Zhongcheng Cui 1,  Tao Zhang 3,  Weiwei Zou 4,  Guanying Han 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Jinzhou Medical University, Jinzhou, China.
  • 2 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China.
  • 3 Department of General Surgery, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China. Electronic address: zhangtao_qdzt@126.com.
  • 4 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China; Medicine-Engineering Integration & Medical Equipment Innovation Institute of Anhui Medical University, Hefei, Anhui, China. Electronic address: zouweiwei@ahmu.edu.cn.
  • 5 Medical College of Jinzhou Medical University, Jinzhou, China; The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China. Electronic address: hgy19800223@163.com.
PMID: 38960210 DOI: 10.1016/j.mcp.2024.101968
Abstract

The close association between organelle interactions, such as mitochondrial-lysosomal interactions, and various diseases, including tumors, remains a challenge for drug discovering and identification. Conventional evaluation methods are often complex and multistep labeling procedures often generate false positives, such as cell damage. To overcome these limitations, we employed a single dual-color reporting molecule called Coupa, which labels mitochondria and lysosomes as blue and red, respectively. This facilitates the evaluation and discovering of drugs targeting mitochondria-lysosome contact (MLC). Using Coupa, we validated the effectiveness of various known antitumor drugs in intervening MLC by assessing their effect on key aspects, such as status, localization, and quantity. This provides evidence for the accuracy and applicability of our dual-color reporting molecule. Notably, we observed that several structural isomers of drugs, including Urolithin (A/B/C), exhibited distinct effects on MLC. In addition, Verteporfin and TEAD were found to induce anti-tumor effects by controlling MLC at the organelle level, suggesting a potential new mechanism of action. Collectively, Coupa offers a novel scientific tool for discovering drugs that target mitochondrial-lysosomal interactions. It not only distinguished the differential effects of structurally similar drugs on the same target, but also reveals new mechanisms underlying the reported antitumor properties of existing drugs. Ultimately, our findings contribute to the advancement of drug discovery and provide valuable insights into the complex interactions between organelles in a disease context.

Keywords

Drug discovering; Lysosome; Mitochondria; Mitochondrial-lysosomal interaction; Sensor.

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