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Article https://doi.org/10.1038/s41467-024-55661-5Polysulfur-based bulking of dynamin-relatedprotein 1 prevents ischemic sulf i decatabolism and heart failure in miceAkiyuki Nishimura1,2,3 , Seiryo Ogata 4 , Xiaokang Tang 1,2,3 ,Kowit Hengphasatporn 5 , Keitaro Umezawa6 , Makoto Sanbo 1 ,Masumi Hirabayashi1 , Yuri Kato 7 , Yuko Ibuki 8 , Yoshito Kumagai 7 ,Kenta Kobayashi1 , Yasunari Kanda 9 , Yasuteru Urano 10,11 ,Yasuteru Shigeta5 , Takaaki Akaike 4& Motohiro Nishida1,2,3,7The presence of redox-active molecules containing catenated sulfur atoms(supersulf i des)inliving organisms hasledtoareviewofthe concepts ofredoxbiology and its translational strategy. Glutathione (GSH) is the body’s primarydetoxif i er and antioxidant, and its oxidized form (GSSG) has been consideredasamarkerofoxidativestatus.However,wereportthatGSSG,butnotreducedGSH, prevents ischemic supersulf i de catabolism-associated heart failure inmale mice by electrophilic modif i cation of dynamin-related protein (Drp1). Inhealthy exercised hearts, the redox-sensitive Cys644 of Drp1 is highlyS-glutathionylated.Nearly40%ofCys644isnormallypolysulf i dated,whichisapreferential target for GSSG-mediated S-glutathionylation. Cys644S-glutathionylation is resistant to Drp1 depolysulf i dation-dependent mito-chondrial hyperf i ssion and myocardial dysfunction caused by hypoxic stress.MD simulation of Drp1 structure and site-directed mutagenetic analysis reveala functional interaction between Cys644 and a critical phosphorylation siteSer637, through Glu640. Bulky modif i cation at Cys644 via polysulf i dation orS-glutathionylationreducesDrp1activitybydisruptingSer637-Glu640-Cys644interaction. Disruption of Cys644 S-glutathionylation nullif i es the cardiopro-tective effect of GSSG against heart failure after myocardial infarction. Ourf i ndings suggest a therapeutic potential of supersulf i de-based Cys bulking onDrp1 for ischemic heart disease.Recent changes in therapeutic strategies for cardiac diseases have ledto a broad acceptance of the concept of heart failure as a metabolicdisease. Since mitochondrial dysfunction is a key feature of thedevelopment of various types of heart failure, mitochondria areexpected as a potent target for heart failure therapy 1,2 . MitochondrialqualityispreciselycontrolledbythefollowingGTPases:mitochondrialf i ssion factors such as dynamin-related protein1 (Drp1) and fusionfactors such as mitofusin 1/2 (Mfn1/2) and optic atrophy 1 (Opa1), andgenetic ablations of any of the GTPases reportedly cause heartfailure 3–5 . We previously found that Drp1 mediates mitochondrialhyperf i ssion-associated myocardial early senescence after myocardialinfarction (MI), leading to chronic heart failure 6 . Hypoxic stress indu-ces Drp1 interaction with actin-binding protein f i lamin A (FLNa), aguanine nucleotide exchange factor for Drp1, and this complex for-mation at the mitochondrial f i ssion site leads to Drp1-dependentmitochondrial f i ssion 6 .Received: 9 May 2023Accepted: 18 December 2024Check for updatesA full list of aff i liations appears at the end of the paper. e-mail: nishida@phar.kyushu-u.ac.jpNature Communications| (2025) 16:276 11234567890():,;1234567890():,;