Proper mitochondrial quality control is indispensable for cardiac homeostasis and defects in mitochondrial dynamics are implicated in the development of cardiac diseases. Our group has investigated the molecular mechanism underlying the development of maladaptive cardiac remodeling, especially myocardial senescence, and found that mitochondrial hyperfission induced by aberrant activation of Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating protein, is a key determinant of cardiac remodeling and fragility. Supersulfides have been recently recognized as a key molecule to regulate redox homeostasis and are abundantly discovered in both prokaryotes and eukaryotes. We found that Drp1 activity is negatively regulated by supersulfide-mediated polysulfidation of Drp1 at Cys⁶²⁴. Ischemic stress induced by myocardial infarction converted supersulfides into hydrogen sulfide, and reduced supersulfides promoted Drp1 hyperactivation via depolysulfidation of Cys⁶²⁴, causing myocardial senescence and cardiac fragility. Exposure of cardiomyocytes to environmental electrophiles such as methylmercury also induced supersulfide depletion and triggered mitochondrial hyperfission-associated myocardial senescence.