A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress
Abstract Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59434-6 |
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| author | Suman Pokhrel Gwangbeom Heo Irimpan Mathews Shun Yokoi Tsutomu Matsui Ayori Mitsutake Soichi Wakatsuki Daria Mochly-Rosen |
| author_facet | Suman Pokhrel Gwangbeom Heo Irimpan Mathews Shun Yokoi Tsutomu Matsui Ayori Mitsutake Soichi Wakatsuki Daria Mochly-Rosen |
| author_sort | Suman Pokhrel |
| collection | DOAJ |
| description | Abstract Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction. |
| format | Article |
| id | doaj-art-85439fe6ff84432f8bc560f3f3dd40a9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-85439fe6ff84432f8bc560f3f3dd40a92025-08-20T03:53:13ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-59434-6A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stressSuman Pokhrel0Gwangbeom Heo1Irimpan Mathews2Shun Yokoi3Tsutomu Matsui4Ayori Mitsutake5Soichi Wakatsuki6Daria Mochly-Rosen7Department of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineStanford Synchrotron Radiation LightsourceBiological Sciences Division, SLAC National Accelerator LaboratoryStanford Synchrotron Radiation LightsourceDepartment of Physics, School of Science and Technology, Meiji UniversityBiological Sciences Division, SLAC National Accelerator LaboratoryDepartment of Chemical and Systems Biology, Stanford University School of MedicineAbstract Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.https://doi.org/10.1038/s41467-025-59434-6 |
| spellingShingle | Suman Pokhrel Gwangbeom Heo Irimpan Mathews Shun Yokoi Tsutomu Matsui Ayori Mitsutake Soichi Wakatsuki Daria Mochly-Rosen A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress Nature Communications |
| title | A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress |
| title_full | A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress |
| title_fullStr | A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress |
| title_full_unstemmed | A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress |
| title_short | A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress |
| title_sort | hidden cysteine in fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress |
| url | https://doi.org/10.1038/s41467-025-59434-6 |
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