Dynamin-related protein 1 (Drp1) is a mitochondrial fission-inducing protein and we previously reported that the activity of Drp1 was critical for the development of heart failure. Recently, cysteine persulfide or polysulfide on proteins [reactive sulfur species (RSS)] have been identified in organisms and cysteine residue of Drp1 is also found to be polysulfidated. However, the role of polysulfidation of Drp1 have been remained to be elusive. Here, I revealed that the change in Drp1 polysulfidation state affected prognosis of pressure overload-induced heart failure.
One of the environmental electrophiles, methylmercury (MeHg), has been known as cardiotoxic agent. Indeed, MeHg-treated mice showed vulnerability to cardiac pressure overload. Interestingly, MeHg treatment induced Drp1 activation and mitochondrial fragmentation accompanied by decreased Drp1 polysulfidation (depolysulfidation). These data suggest that depolysulfidation of Drp1 increase its activity for mitochondrial fission and induce cardiac vulnerability. In addition, sulfide donor sodium hydrogen sulfide (NaHS) treatment restored Drp1 polysulfidation, inhibiting MeHg-induced Drp1 activation and cardiac vulnerability against pressure overload. This result indicates that Drp1 polysulidation state is critical for cardiac robustness.
These findings suggest that formation of RSS can be important for the development of heart failure. Several pathways for RSS formation have been recently identified and these processes can be novel therapeutic target for heart failure.