Regulation of cardiac homeostasis by sulfur metabolism and its disruption by environmental electrophiles

<p>We are exposed to a variety of environmental factors in our daily lives. A wide variety of epidemiological studies have suggested that environmental electrophiles such as methylmercury (MeHg) and cigarette sidestream smoke (CSS) disrupt our homeostasis and increase the risk of cardiovascular disease. However, the underlying mechanism is unclear. We previously identified that aberrant activation of Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating protein, is a key determinant of cardiac remodeling and fragility. Here we show that supersulfides that are redox-active sulfur metabolites have a critical role in the mitochondrial quality and cardiac homeostasis and exposure to environmental electrophiles such as MeHg and CSS increased cardiac risk by disrupting supersulfide-mediated mitochondrial quality.</p><p>Supersulfides highly exist in healthy cardiomyocytes and maintained the proper mitochondrial fission and fusion balance by regulating Drp1 activity through Cys⁶⁴⁴ polysulfidation. In a failing heart, supersulfides were catabolized to hydrogen sulfides, and this change in sulfide metabolism promoted Cys⁶⁴⁴ depolysulfidation of Drp1, which led to dysfunctions of mitochondria and cardiomyocytes. Supersulfide administration reversed electrophile-evoked mitochondrial dysfunction and improved the cardiac function of heart failure model mice. These results suggest that depolysulfidation of Drp1 at Cys⁶⁴⁴ by environmental stress such as MeHg increases cardiac fragility.</p>