Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
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. Becaus...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40043-0 |
| _version_ | 1827895038392139776 |
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| author | Luis Rios Suman Pokhrel Sin-Jin Li Gwangbeom Heo Bereketeab Haileselassie Daria Mochly-Rosen |
| author_facet | Luis Rios Suman Pokhrel Sin-Jin Li Gwangbeom Heo Bereketeab Haileselassie Daria Mochly-Rosen |
| author_sort | Luis Rios |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:16:00Z |
| format | Article |
| id | doaj.art-8067fdebdbc2477ca2f4060fcace8ed0 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T22:16:00Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8067fdebdbc2477ca2f4060fcace8ed02023-07-23T11:19:12ZengNature PortfolioNature Communications2041-17232023-07-0114111610.1038/s41467-023-40043-0Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunctionLuis Rios0Suman Pokhrel1Sin-Jin Li2Gwangbeom Heo3Bereketeab Haileselassie4Daria Mochly-Rosen5Department of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Pediatrics, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Pediatrics, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-023-40043-0 |
| spellingShingle | Luis Rios Suman Pokhrel Sin-Jin Li Gwangbeom Heo Bereketeab Haileselassie Daria Mochly-Rosen Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction Nature Communications |
| title | Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction |
| title_full | Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction |
| title_fullStr | Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction |
| title_full_unstemmed | Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction |
| title_short | Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction |
| title_sort | targeting an allosteric site in dynamin related protein 1 to inhibit fis1 mediated mitochondrial dysfunction |
| url | https://doi.org/10.1038/s41467-023-40043-0 |
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