Mitochondrial hydropersulfides (RSSH)

Mitochondrial hydropersulfides, such as cysteine hydropersulfide (Cys-SSH), are a class of reactive sulfur species (RSS) that play a pivotal role in maintaining mitochondrial redox homeostasis (Ida et al., 2014, PNAS). These molecules are primarily synthesized within the mitochondria by the enzyme cysteinyl-tRNA synthetase 2 (CARS2), which utilizes cysteine as a substrate to produce Cys-SSH (Akaike et al., 2017, Nature Communications). They function as potent antioxidants, outperforming traditional thiols like glutathione in scavenging reactive oxygen species and protecting mitochondrial DNA and proteins from oxidative damage. Furthermore, mitochondrial persulfides act as signaling molecules by mediating protein persulfidation, a post-translational modification that regulates the activity of enzymes involved in the electron transport chain and metabolic pathways (Zivanovic et al., 2019, Cell Metabolism). Dysregulation of these sulfur species is implicated in the pathogenesis of various conditions, including cancer, where they support metabolic reprogramming, and neurodegenerative diseases characterized by mitochondrial dysfunction. Therapeutic strategies targeting this system involve the use of mitochondria-targeted donors, such as AP39, which release hydrogen sulfide or sulfane sulfur to replenish persulfide pools and restore bioenergetic function (Szabo et al., 2014, Molecular Medicine Reports). Consequently, mitochondrial persulfides represent a novel frontier in pharmacology for treating diseases linked to oxidative stress and impaired energy metabolism.

Other names

Mitochondrial persulfide-containing moleculesReactive sulfur speciesRSSSulfane sulfurCysteine hydropersulfideGlutathione hydropersulfideMitochondrial RSSH

Enhancement of mitochondrial sulfane sulfur pools to promote protein persulfidation and neutralize reactive oxygen species (Filipovic et al., 2018, Chemical Reviews).