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

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Listed:
  • Akiyuki Nishimura

    (National Institutes of Natural Sciences (NINS)
    NINS
    SOKENDAI (The Graduate University for Advanced Studies))

  • Seiryo Ogata

    (Tohoku University)

  • Xiaokang Tang

    (National Institutes of Natural Sciences (NINS)
    NINS
    SOKENDAI (The Graduate University for Advanced Studies))

  • 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
    The University of Tokyo)

  • Yasuteru Shigeta

    (University of Tsukuba)

  • Takaaki Akaike

    (Tohoku University)

  • Motohiro Nishida

    (National Institutes of Natural Sciences (NINS)
    NINS
    SOKENDAI (The Graduate University for Advanced Studies)
    Kyushu University)

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.

Suggested Citation

  • Akiyuki Nishimura & Seiryo Ogata & Xiaokang Tang & Kowit Hengphasatporn & Keitaro Umezawa & Makoto Sanbo & Masumi Hirabayashi & Yuri Kato & Yuko Ibuki & Yoshito Kumagai & Kenta Kobayashi & Yasunari Ka, 2025. "Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55661-5
    DOI: 10.1038/s41467-024-55661-5
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    References listed on IDEAS

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    1. Raghav Kalia & Ray Yu-Ruei Wang & Ali Yusuf & Paul V. Thomas & David A. Agard & Janet M. Shaw & Adam Frost, 2018. "Structural basis of mitochondrial receptor binding and constriction by DRP1," Nature, Nature, vol. 558(7710), pages 401-405, June.
    2. Takaaki Akaike & Tomoaki Ida & Fan-Yan Wei & Motohiro Nishida & Yoshito Kumagai & Md. Morshedul Alam & Hideshi Ihara & Tomohiro Sawa & Tetsuro Matsunaga & Shingo Kasamatsu & Akiyuki Nishimura & Masano, 2017. "Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
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