2. Academic Validation
  3. A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress

A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress

  • Nat Commun. 2025 May 6;16(1):4187. doi: 10.1038/s41467-025-59434-6.
Suman Pokhrel # 1 2,  Gwangbeom Heo # 1,  Irimpan Mathews 3,  Shun Yokoi 2 4 5,  Tsutomu Matsui 3,  Ayori Mitsutake 5,  Soichi Wakatsuki 6 7,  Daria Mochly-Rosen 8
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
  • 3 Stanford Synchrotron Radiation Lightsource, Menlo Park, CA, USA.
  • 4 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Department of Physics, School of Science and Technology, Meiji University, Kanagawa, Japan.
  • 6 Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA. soichi.wakatsuki@stanford.edu.
  • 7 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. soichi.wakatsuki@stanford.edu.
  • 8 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA. mochly@stanford.edu.
  • # Contributed equally.
PMID: 40328741 DOI: 10.1038/s41467-025-59434-6
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.

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