Redox regulation of mitochondrial quality as a therapeutic target of cardiac senescence

抄録

Mitochondria are dynamic organelles that continuously undergo fission and fusion, which are necessary for maintaining bioenergetic homeostasis and robustness in heart. Mitochondrial fission and fusion cycle is precisely regulated by three GTP-binding proteins, dynamin-related protein 1 (Drp1), mitofusins (Mfn1 and mfn2) and optic atrophy 1 (Opa1), and these three G proteins have redox-sensitive cysteine (Cys) residues. Especially, mitochondria predominantly show tubular form in adult cardiomyocytes and are reported to be fragmented by the exposure to electrophilic chemical substances produced by hypoxic and hyperglycemic stress. We found that depolysulfidation of Cys624 on Drp1, caused by endogenous or exogenous electrophiles, increased basal Drp1 GTPase activity as well as cardiac vulnerability to hemodynamic load in mouse hearts. Reactive sulfide species such as Cys persulfide produced through mitochondria-localized Cys tRNA synthetase (CARS2) preferentially eliminate and metabolize electrophiles. Protein persulfide detection assay revealed that endogenous Drp1 protein possesses several Cys persulfides in a CARS2) dependent manner, and exposure to environmental electrophiles such as methylmercury (MeHg) reduced Drp1 persulfide levels. Supplementation of sulfur to Cys-624 by exogenous treatment with NaHS completely abolished MeHg-induced sulfur deprivation of Drp1 protein as well as exacerbation of myocardial injury induced by mechanical stress. These results strongly suggest that formation of Drp1 Cys624 polysulfidation negatively regulates electrophile-mediated mitochondrial hyperfission and cardiac stress resistance against environmental stresses.