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Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction

Author

Listed:
  • Luis Rios

    (Stanford University School of Medicine)

  • Suman Pokhrel

    (Stanford University School of Medicine)

  • Sin-Jin Li

    (Stanford University School of Medicine
    National Taiwan University)

  • Gwangbeom Heo

    (Stanford University School of Medicine)

  • Bereketeab Haileselassie

    (Stanford University School of Medicine)

  • Daria Mochly-Rosen

    (Stanford University School of Medicine)

Abstract

The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110’s benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110’s benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.

Suggested Citation

  • Luis Rios & Suman Pokhrel & Sin-Jin Li & Gwangbeom Heo & Bereketeab Haileselassie & Daria Mochly-Rosen, 2023. "Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40043-0
    DOI: 10.1038/s41467-023-40043-0
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    References listed on IDEAS

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    1. Raghav Kalia & Ray Yu-Ruei Wang & Ali Yusuf & Paul V. Thomas & David A. Agard & Janet M. Shaw & Adam Frost, 2018. "Structural basis of mitochondrial receptor binding and constriction by DRP1," Nature, Nature, vol. 558(7710), pages 401-405, June.
    2. Zhenlin Yang & Shuo Han & Max Keller & Anette Kaiser & Brian J. Bender & Mathias Bosse & Kerstin Burkert & Lisa M. Kögler & David Wifling & Guenther Bernhardt & Nicole Plank & Timo Littmann & Peter Sc, 2018. "Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor," Nature, Nature, vol. 556(7702), pages 520-524, April.
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