Nature Chemical Biology, 12 January, 2023, DOI：https://doi.org/10.1038/s41589-022-01224-y
Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction
Yingjie Guo, Huan Zhang, Chen Yan, Birong Shen, Yue Zhang, Xiangyang Guo, Sha Sun, Fan Yu, Jiayun Yan, Ronghe Liu, Qianping Zhang, Di Zhang, Haiyang Liu, Yang Liu, Yaoyao Zhang, Wenlei Li, Jiangyu Qin, He Lv, Zhaoxia Wang, Yun Yuan, Jie-Feng Yang, Ya-Ting Zhong, Song Gao, Bing Zhou, Lei Liu, Deling Kong, Xiaojiang Hao, Junjie Hu & Quan Chen
Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.