Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice

Akiyuki Nishimura, Seiryo Ogata, Xiaokang Tang, Kowit Hengphasatporn, Keitaro Umezawa, Makoto Sanbo, Masumi Hirabayashi, Yuri Kato, Yuko Ibuki, Yoshito Kumagai, Kenta Kobayashi, Yasunari Kanda, Yasuteru Urano, Yasuteru Shigeta, Takaaki Akaike and Motohiro Nishida ()
Additional contact information
Akiyuki Nishimura: National Institutes of Natural Sciences (NINS)
Seiryo Ogata: Tohoku University
Xiaokang Tang: National Institutes of Natural Sciences (NINS)
Kowit Hengphasatporn: University of Tsukuba
Keitaro Umezawa: Tokyo Metropolitan Institute for Geriatrics and Gerontology
Makoto Sanbo: National Institutes of Natural Sciences (NINS)
Masumi Hirabayashi: National Institutes of Natural Sciences (NINS)
Yuri Kato: Kyushu University
Yuko Ibuki: University of Shizuoka
Yoshito Kumagai: Kyushu University
Kenta Kobayashi: National Institutes of Natural Sciences (NINS)
Yasunari Kanda: National Institute of Health Sciences (NIHS)
Yasuteru Urano: The University of Tokyo
Yasuteru Shigeta: University of Tsukuba
Takaaki Akaike: Tohoku University
Motohiro Nishida: National Institutes of Natural Sciences (NINS)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review of the concepts of redox biology and its translational strategy. Glutathione (GSH) is the body’s primary detoxifier and antioxidant, and its oxidized form (GSSG) has been considered as a marker of oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure in male mice by electrophilic modification of dynamin-related protein (Drp1). In healthy exercised hearts, the redox-sensitive Cys644 of Drp1 is highly S-glutathionylated. Nearly 40% of Cys644 is normally polysulfidated, which is a preferential target for GSSG-mediated S-glutathionylation. Cys644 S-glutathionylation is resistant to Drp1 depolysulfidation-dependent mitochondrial hyperfission and myocardial dysfunction caused by hypoxic stress. MD simulation of Drp1 structure and site-directed mutagenetic analysis reveal a functional interaction between Cys644 and a critical phosphorylation site Ser637, through Glu640. Bulky modification at Cys644 via polysulfidation or S-glutathionylation reduces Drp1 activity by disrupting Ser637-Glu640-Cys644 interaction. Disruption of Cys644 S-glutathionylation nullifies the cardioprotective effect of GSSG against heart failure after myocardial infarction. Our findings suggest a therapeutic potential of supersulfide-based Cys bulking on Drp1 for ischemic heart disease.

Date: 2025
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DOI: 10.1038/s41467-024-55661-5

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