Moonlighting Functions of Cysteinyl-tRNA Synthetases: Cycteine Hydropersulfide Production and Regulation of Mitochondrial Biogenesis and Bioenergetics

Abstract

Hydrogen sulfide and reactive persulfide species such as cysteine hydropersulfide (CysSSH) are reportedly formed endogenously in prokaryotic and eukaryotic cells and in mammals in vivo. The chemical properties and abundance of these species suggest a pivotal role for reactive persulfides (i.e., various compounds containing -SSH) in different cellular regulatory processes. We proposed that CysSSH and related reactive sulfur species can behave as potent antioxidants and cellular protectants and may function as redox signaling intermediates. Extensive persulfide formation is now apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is thus far believed to result from post-translational modifications involving hydrogen sulfide-related chemistry. Here, we discovered moonlighting (dual) functions of cysteinyl-tRNA synthetases (CARSs), serve as the principal cysteine persulfide synthase (CPERS) in vivo. Targeted disruption of a gene encoding mitochondrial CARS (CARS2) in mice and human cells revealed that persulfides derived from CARS2 are critically involved in the mitochondrial biogenesis and energy metabolism, i.e., bioenergetics, which is known for a long time as sulfur respiration in anaerobic bacteria. Further investigating CARS-dependent persulfide production will clarify aberrant redox signaling that we may call as sulfur stress and a unique energy metabolism in mammals.