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

Nishimura, Akiyuki; Ogata, Seiryo; Tang, Xiaokang; Hengphasatporn, Kowit; Umezawa, Keitaro; Sanbo, Makoto; Hirabayashi, Masumi; Kato, Yuri; Ibuki, Yuko; Kumagai, Yoshito; Kobayashi, Kenta; Kanda, Yasunari; Urano, Yasuteru; Shigeta, Yasuteru; Akaike, Takaaki; Nishida, Motohiro

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. The oxidized glutathione (GSSG) has been considered as a marker of oxidative status. Here the authors show that GSSG, but not GSH, improves ischemic heart failure by inhibiting mitochondrial fission through polysulfur-based S-glutathionylation of Drp1 at Cys644.

CORONARY disease; MITOCHONDRIAL dynamics; MYOCARDIAL ischemia; HEART failure; LIFE sciences

Nature Communications, 2025, Vol 16, p1

2041-1723

Academic Journal

10.1038/s41467-024-55661-5