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

doi: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^*

^*Corresponding author for this work

School of Engineering Medicine

State Key Laboratory of Membrane Biology
CAS - Institute of Zoology
State Key Laboratory of Medicinal Chemical Biology
Nankai University
University of Chinese Academy of Sciences
National Laboratory of Biomacromolecules
State Key Laboratory of Phytochemistry and Plant Resources
CAS - Kunming Institute of Botany
Department of Physiology and Pathophysiology
Tianjin Medical University
Interdisciplinary Center of Cell Response
Beijing Key Laboratory of Neurovascular Disease Discovery
Peking University
State Key Laboratory of Oncology in South China
Sun Yat-Sen University Cancer Center

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

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. [Figure not available: see fulltext.]

Original language	English
Pages (from-to)	468-477
Number of pages	10
Journal	Nature Chemical Biology
Volume	19
Issue number	4
DOIs	https://doi.org/10.1038/s41589-022-01224-y
State	Published - Apr 2023

Access to Document

10.1038/s41589-022-01224-y

Cite this

@article{856c219be8ca4dc1961d099d9e77c938,

title = "Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction",

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. [Figure not available: see fulltext.]",

author = "Yingjie Guo and Huan Zhang and Chen Yan and Birong Shen and Yue Zhang and Xiangyang Guo and Sha Sun and Fan Yu and Jiayun Yan and Ronghe Liu and Qianping Zhang and Di Zhang and Haiyang Liu and Yang Liu and Yaoyao Zhang and Wenlei Li and Jiangyu Qin and He Lv and Zhaoxia Wang and Yun Yuan and Yang, \{Jie Feng\} and Zhong, \{Ya Ting\} and Song Gao and Bing Zhou and Lei Liu and Deling Kong and Xiaojiang Hao and Junjie Hu and Quan Chen",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = apr,

doi = "10.1038/s41589-022-01224-y",

language = "英语",

volume = "19",

pages = "468--477",

journal = "Nature Chemical Biology",

issn = "1552-4450",

publisher = "Nature Research",

number = "4",

}

Guo, Y, Zhang, H, Yan, C, Shen, B, Zhang, Y, Guo, X, Sun, S, Yu, F, Yan, J, Liu, R, Zhang, Q, Zhang, D, Liu, H, Liu, Y, Zhang, Y, Li, W, Qin, J, Lv, H, Wang, Z, Yuan, Y, Yang, JF, Zhong, YT, Gao, S, Zhou, B, Liu, L, Kong, D, Hao, X, Hu, J & Chen, Q 2023, 'Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction', Nature Chemical Biology, vol. 19, no. 4, pp. 468-477. https://doi.org/10.1038/s41589-022-01224-y

TY - JOUR

T1 - Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction

AU - Guo, Yingjie

AU - Zhang, Huan

AU - Yan, Chen

AU - Shen, Birong

AU - Zhang, Yue

AU - Guo, Xiangyang

AU - Sun, Sha

AU - Yu, Fan

AU - Yan, Jiayun

AU - Liu, Ronghe

AU - Zhang, Qianping

AU - Zhang, Di

AU - Liu, Haiyang

AU - Liu, Yang

AU - Zhang, Yaoyao

AU - Li, Wenlei

AU - Qin, Jiangyu

AU - Lv, He

AU - Wang, Zhaoxia

AU - Yuan, Yun

AU - Yang, Jie Feng

AU - Zhong, Ya Ting

AU - Gao, Song

AU - Zhou, Bing

AU - Liu, Lei

AU - Kong, Deling

AU - Hao, Xiaojiang

AU - Hu, Junjie

AU - Chen, Quan

PY - 2023/4

Y1 - 2023/4

N2 - 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. [Figure not available: see fulltext.]

AB - 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. [Figure not available: see fulltext.]

UR - https://www.scopus.com/pages/publications/85146152388

U2 - 10.1038/s41589-022-01224-y

DO - 10.1038/s41589-022-01224-y

M3 - 文章

C2 - 36635564

AN - SCOPUS:85146152388

SN - 1552-4450

VL - 19

SP - 468

EP - 477

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 4

ER -

Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction

Abstract

Access to Document

Other files and links

Fingerprint

Cite this