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

Pokhrel, Suman; Heo, Gwangbeom; Mathews, Irimpan; Yokoi, Shun; Matsui, Tsutomu; Mitsutake, Ayori; Wakatsuki, Soichi; Mochly-Rosen, Daria

doi:10.1038/s41467-025-59434-6

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

Journal Article · Tue May 06 04:00:00 EDT 2025 · Nature Communications

DOI:https://doi.org/10.1038/s41467-025-59434-6· OSTI ID:2575397

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Stanford Univ., CA (United States). School of Medicine; SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Stanford Univ., CA (United States). School of Medicine
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Stanford Univ., CA (United States). School of Medicine; Meiji University, Kanagawa (Japan)
Meiji University, Kanagawa (Japan)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Stanford Univ., CA (United States). School of Medicine

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOD; JSPS KAKENHI; JST SICORP; USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2575397

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 16; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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