TitleChemical inhibition of mitochondrial fission via targeting the DRP1-receptor interaction
AuthorsYang, Jun
Chen, Peihao
Cao, Yu
Liu, Shanshan
Wang, Wei
Li, Lin
Li, Jiaojiao
Jiang, Zhaodi
Ma, Yan
Chen, She
Zheng, Sanduo
Qi, Xiangbing
Jiang, Hui
AffiliationTsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China
Natl Inst Biol Sci, Beijing 102206, Peoples R China
Peking Univ, Sch Life Sci, Beijing, Peoples R China
Beijing Normal Univ, Coll Life Sci, Beijing, Peoples R China
Beijing Key Lab Cell Biol Anim Aging, Beijing 102206, Peoples R China
Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing 102206, Peoples R China
KeywordsDOMINANT OPTIC ATROPHY
DYNAMIN-RELATED PROTEIN-1
DIVISION DYNAMIN
DRP1 RECRUITMENT
OPA1 MUTATIONS
MID51
MFF
GTPASE
MID49
FUSION
Issue Date16-Mar-2023
PublisherCELL CHEMICAL BIOLOGY
AbstractMitochondrial fission is critical for mitochondrial dynamics and homeostasis. The dynamin superfamily GTPase DRP1 is recruited by three functionally redundant receptors, MFF, MiD49, and MiD51, to mitochon-dria to drive fission. Here, we exploit high-content live-cell imaging to screen for mitochondrial fission inhib-itors and have developed a covalent compound, mitochondrial division inhibitor (MIDI). MIDI treatment potently blocks mitochondrial fragmentation induced by mitochondrial toxins and restores mitochondrial morphology in fusion-defective cells carrying pathogenic mitofusin and OPA1 mutations. Mechanistically, MIDI does not affect DRP1 tetramerization nor DRP1 GTPase activity but does block DRP1 recruitment to mitochondria. Subsequent biochemical and cellular characterizations reveal an unexpected mechanism that MIDI targets DRP1 interaction with multiple receptors via covalent interaction with DRP1-C367. Taken together, beyond developing a potent mitochondrial fission inhibitor that profoundly impacts mitochondrial morphogenesis, our study establishes proof of concept for developing protein-protein interaction inhibitors targeting DRP1.
URIhttp://hdl.handle.net/20.500.11897/674703
ISSN2451-9456
DOI10.1016/j.chembiol.2023.02.002
IndexedSCI(E)
Appears in Collections:生命科学学院

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