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
发表期刊	NATURE CHEMICAL BIOLOGY
ISSN	1552-4469
卷号	19 期号:4 页码:468-+
摘要	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.
关键词	ENDOPLASMIC-RETICULUM PROVIDE INSIGHT MITOFUSIN 2 MFN1 DYNAMICS REQUIRES DEFECTS FISSION CELLS
学科领域	Biochemistry & Molecular Biology
DOI	10.1038/s41589-022-01224-y
收录类别	SCI
WOS记录号	WOS:000913493200003
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75538
专题	中国科学院昆明植物研究所
推荐引用方式 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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