↵* Present address: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8575, Japan. Although the widespread environmental contaminant methylmercury is largely associated with neurotoxic effects, it is also associated with increased risk for cardiovascular disease. Nishimura et al. found that mice exposed to a dose of methylmercury that was too low to cause neurotoxicity were more vulnerable to heart failure in response to pressure overload. Methylmercury removed a polysulfide group from Drp1, thereby removing an inhibitory brake on this protein, which resulted in increased Drp1-mediated mitochondrial fission. Treating mice or human cardiomyocytes with a polysulfide group–releasing compound reversed fragility to mechanical overload induced by methylmercury. These results provide a molecular mechanism for the cardiotoxic effects of methylmercury and a possible strategy to avert these effects. Chronic exposure to methylmercury (MeHg), an environmental electrophilic pollutant, reportedly increases the risk of human cardiac events. We report that exposure to a low, non-neurotoxic dose of MeHg precipitated heart failure induced by pressure overload in mice. Expo...