Supersulfide catabolism underlies cardiac vulnerability to ischemic and electrophilic stress

<p>The robustness of cardiomyocytes is supported by their superior redox homeostasis, and disruption of redox homeostasis leads to the onset and progression of cardiac disease. Supersulfides, which include catenated sulfur atoms (R-S_nSH) such as cysteine persulfide (Cys-SSH), have been recently identified as highly reactive sulfur metabolites and recognized as a key molecule to regulate redox homeostasis. This study aimed to elucidate the role of sulfur metabolism in maintaining cardiac robustness, and the impact of abnormal sulfur metabolism on ischemic and electrophilic stress-mediated cardiac dysfunction.</p><p>Supersulfides are reduced to hydrogen sulfides in cardiomyocytes after ischemic and electrophilic stress. This supersulfide catabolism decreased the contractile function of cardiomyocytes through mitochondrial hyperfission. We also found that the depletion of supersulfides promotes mitochondrial fission by decreasing polysulfidation of mitochondrial fission factor Drp1 at Cys644.</p><p>Our results suggest that the redox modification of Drp1 Cys644 has a pivotal role in the ischemic and electrophilic tolerance of cardiomyocytes. We found that this polysulfidated Cys644 is modified by S-glutathionylation. Drp1 was glutathionylated by oxidized GSSG but not reduced GSH. GSSG-mediated Drp1 glutathionylation protected cardiac function against ischemic and electrophilic stress in vitro and in vivo. These results suggest that sulfur metabolism has a pivotal role in ischemic and electrophilic stress-mediated cardiac dysfunction through Drp1 Cys644 redox modification.</p>