TY - JOUR
T1 - A dual-labeling molecule for efficient drug discovery of mitochondrial-lysosomal interactions
AU - Wu, Jinfang
AU - Wang, Xiaolei
AU - Li, Xiang
AU - Zhu, Zixuan
AU - Cui, Zhongcheng
AU - Zhang, Tao
AU - Zou, Weiwei
AU - Han, Guanying
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/8
Y1 - 2024/8
N2 - 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.
AB - 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.
KW - Drug discovering
KW - Lysosome
KW - Mitochondria
KW - Mitochondrial-lysosomal interaction
KW - Sensor
UR - http://www.scopus.com/inward/record.url?scp=85197629284&partnerID=8YFLogxK
U2 - 10.1016/j.mcp.2024.101968
DO - 10.1016/j.mcp.2024.101968
M3 - Article
C2 - 38960210
AN - SCOPUS:85197629284
SN - 0890-8508
VL - 76
JO - Molecular and Cellular Probes
JF - Molecular and Cellular Probes
M1 - 101968
ER -