. 2023 Apr;19(4):468-477.

doi: 10.1038/s41589-022-01224-y. Epub 2023 Jan 12.

Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction

Yingjie Guo^#^{1

2

3}, Huan Zhang^#^{3

4}, Chen Yan^#⁵, Birong Shen^#⁴, Yue Zhang⁶, Xiangyang Guo^{4

7}, Sha Sun⁴, Fan Yu⁷, Jiayun Yan^{3

4}, Ronghe Liu^{3

4}, Qianping Zhang⁷, Di Zhang⁷, Haiyang Liu⁵, Yang Liu^{2

7}, Yaoyao Zhang⁷, Wenlei Li⁷, Jiangyu Qin⁶, He Lv⁸, Zhaoxia Wang⁸, Yun Yuan⁸, Jie-Feng Yang⁹, Ya-Ting Zhong⁹, Song Gao⁹, Bing Zhou¹⁰, Lei Liu^{1

3}, Deling Kong⁷, Xiaojiang Hao¹¹, Junjie Hu^{12

13}, Quan Chen^{14

15}

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁵ State Key Laboratory of Phytochemistry and Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
⁶ Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
⁷ Interdisciplinary Center of Cell Response, College of Life Sciences, Nankai University, Tianjin, China.
⁸ Beijing Key Laboratory of Neurovascular Disease Discovery, Department of Neurology, Peking University First Hospital, Beijing, China.
⁹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
¹⁰ Beijing Advanced Innovation Center for Big Data-Based Interdisciplinary Innovation Institute of Medicine and Engineering Interdisciplinary, Beihang University, Beijing, China.
¹¹ State Key Laboratory of Phytochemistry and Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. haoxj@mail.kib.ac.cn.
¹² University of Chinese Academy of Sciences, Beijing, China. huj@ibp.ac.cn.
¹³ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. huj@ibp.ac.cn.
¹⁴ State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China. chenq@nankai.edu.cn.
¹⁵ Interdisciplinary Center of Cell Response, College of Life Sciences, Nankai University, Tianjin, China. chenq@nankai.edu.cn.

^# Contributed equally.

PMID: 36635564
DOI: 10.1038/s41589-022-01224-y

Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction

Yingjie Guo et al. Nat Chem Biol. 2023 Apr.

. 2023 Apr;19(4):468-477.

doi: 10.1038/s41589-022-01224-y. Epub 2023 Jan 12.

Authors

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁵ State Key Laboratory of Phytochemistry and Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
⁶ Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
⁷ Interdisciplinary Center of Cell Response, College of Life Sciences, Nankai University, Tianjin, China.
⁸ Beijing Key Laboratory of Neurovascular Disease Discovery, Department of Neurology, Peking University First Hospital, Beijing, China.
⁹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
¹⁰ Beijing Advanced Innovation Center for Big Data-Based Interdisciplinary Innovation Institute of Medicine and Engineering Interdisciplinary, Beihang University, Beijing, China.
¹¹ State Key Laboratory of Phytochemistry and Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. haoxj@mail.kib.ac.cn.
¹² University of Chinese Academy of Sciences, Beijing, China. huj@ibp.ac.cn.
¹³ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. huj@ibp.ac.cn.
¹⁴ State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China. chenq@nankai.edu.cn.
¹⁵ Interdisciplinary Center of Cell Response, College of Life Sciences, Nankai University, Tianjin, China. chenq@nankai.edu.cn.

^# Contributed equally.

PMID: 36635564
DOI: 10.1038/s41589-022-01224-y

Erratum in

Publisher Correction: Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.
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. Guo Y, et al. Nat Chem Biol. 2023 Apr;19(4):530. doi: 10.1038/s41589-023-01294-6. Nat Chem Biol. 2023. PMID: 36813989 No abstract available.

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.

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