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. Exposure to MeHg
at 10 ppm did not induce
weight loss typical of higher doses but caused mitochondrial hyperfission in myocardium through the activation of Drp1 by its
guanine nucleotide exchange factor filamin-A. Treatment of neonatal rat cardiomyocytes with
cilnidipine, an inhibitor of the interaction between Drp1 and
filamin-A, suppressed mitochondrial hyperfission caused by low-dose MeHg exposure. Modification of
cysteine residues in
proteins with polysulfides is important for redox signaling and mitochondrial homeostasis in mammalian cells. We found that MeHg targeted rat Drp1 at Cys624, a redox-sensitive residue whose SH side chain forms a bulky and nucleophilic
polysulfide (Cys624-S(n)H). MeHg exposure induced the depolysulfidation of Cys624-S(n)H in Drp1, which led to
filamin-dependent activation of Drp1 and mitochondrial hyperfission. Treatment with
NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624-S(n)H by low-dose MeHg increases cardiac fragility to mechanical load through
filamin-dependent mitochondrial hyperfission.