2. Academic Validation
  3. Chemical inhibition of mitochondrial fission via targeting the DRP1-receptor interaction

Chemical inhibition of mitochondrial fission via targeting the DRP1-receptor interaction

  • Cell Chem Biol. 2023 Mar 16;30(3):278-294.e11. doi: 10.1016/j.chembiol.2023.02.002.
Jun Yang 1,  Peihao Chen 2,  Yu Cao 3,  Shanshan Liu 4,  Wei Wang 2,  Lin Li 4,  Jiaojiao Li 4,  Zhaodi Jiang 5,  Yan Ma 5,  She Chen 5,  Sanduo Zheng 5,  Xiangbing Qi 6,  Hui Jiang 7
Affiliations

Affiliations

  • 1 School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China.
  • 2 National Institute of Biological Sciences, Beijing 102206, China; School of Life Sciences, Peking University, Beijing, China.
  • 3 National Institute of Biological Sciences, Beijing 102206, China; College of Life Sciences, Beijing Normal University, Beijing, China.
  • 4 National Institute of Biological Sciences, Beijing 102206, China.
  • 5 National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • 6 National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address: qixiangbing@nibs.ac.cn.
  • 7 School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address: jianghui@nibs.ac.cn.
PMID: 36827981 DOI: 10.1016/j.chembiol.2023.02.002
Abstract

Mitochondrial 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 mitochondria to drive fission. Here, we exploit high-content live-cell imaging to screen for mitochondrial fission inhibitors 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.

Keywords

DRP1 inhibitor; MFF; MIDI; MiD49/51; OPA1; mitochondrial dynamics; mitochondrial fission; mitofusin.

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