Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction

doi:10.1038/s41589-022-01224-y

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	Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction
	Guo,Yingjie; Zhang,Huan; Yan,Chen; Shen,Birong; Zhang,Yue; Guo,Xiangyang; Sun,Sha; Yu,Fan; Yan,Jiayun; Liu,Ronghe; Zhang,Qianping; Zhang,Di; Liu,Haiyang; Liu,Yang; Zhang,Yaoyao; Li,Wenlei; Qin,Jiangyu; Lv,He; Wang,Zhaoxia; Yuan,Yun; Yang,Jie-Feng; Zhong,Ya-Ting; Gao,Song; Zhou,Bing; Liu,Lei; Kong,Deling; Hao,Xiaojiang; Hu,Junjie; Chen,Quan
	2023
Source Publication	NATURE CHEMICAL BIOLOGY
ISSN	1552-4469
Volume	19 Issue:4 Pages:468-+
Abstract	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.
Keyword	ENDOPLASMIC-RETICULUM PROVIDE INSIGHT MITOFUSIN 2 MFN1 DYNAMICS REQUIRES DEFECTS FISSION CELLS
Subject Area	Biochemistry & Molecular Biology
DOI	10.1038/s41589-022-01224-y
Indexed By	SCI
WOS ID	WOS:000913493200003
Citation statistics
Document Type	期刊论文
Identifier	http://ir.kib.ac.cn/handle/151853/75538
Collection	中国科学院昆明植物研究所
Recommended Citation GB/T 7714	Guo,Yingjie,Zhang,Huan,Yan,Chen,et al. Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction[J]. NATURE CHEMICAL BIOLOGY,2023,19(4):468-+.
APA	Guo,Yingjie.,Zhang,Huan.,Yan,Chen.,Shen,Birong.,Zhang,Yue.,...&Chen,Quan.(2023).Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.NATURE CHEMICAL BIOLOGY,19(4),468-+.
MLA	Guo,Yingjie,et al."Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction".NATURE CHEMICAL BIOLOGY 19.4(2023):468-+.

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