Title:

Cysteinyl-tRNA synthetase (CARS) moonlighting mitochondrial biogenesis and energy metabolism via cysteine persulfide production

 

Speaker:

Takaaki Akaike
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan

 

Abstract:

Reactive sulfide species such as hydrogen sulfide and cysteine hydropersulfide (CysSSH) are found physiologically in prokaryotes, eukaryotic cells, and mammalian tissues (1-3). Previously, we unequivocally verified the presence of remarkable amounts of CysSSH, glutathione persulfide (GSSH), and longer chain sulfur compounds (polysulfides, including CysS/GS-(S)n-H) in cultured cells and human tissues in vivo (2, 3). The chemical properties and abundance of these species suggest a pivotal role for reactive persulfides (i.e., compounds containing an –SSH group) in cell-regulatory processes. Little is known about its biosynthesis and physiological functions, however. Researchers proposed that CysSSH and related species can behave as potent antioxidants and cellular protectants and may function as redox signaling intermediates (3). Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here, we discovered moonlighting (dual) functions of cysteinyl-tRNA synthetases (CARSs), that is an effective CysSSH biosynthesis from the substrate L-cysteine (Akaike, T. et al. Nature Comms, in revision). Targeted disruption of genes encoding mitochondrial CARSs in mice and human cells revealed the major role of CARSs in endogenous CysSSH production, which suggests that CARSs serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational protein polysulfidation and are involved in regulating of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction.

 

References:
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