Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells

Abstract

Cysteine persulfide and polysulfide are produced in cells and exist in abundance in both low MW and protein fractions. However, the mechanism of regulation of the formation of cellular cysteine polysulfides and the physiological functions of cysteine persulfides/polysulfides produced in cells are not fully understood. We recently demonstrated that cysteinyl-tRNA synthetase (CARS) is a novel cysteine persulfide synthase. CARS is involved in protein polysulfidation that is coupled with translation. In particular, mitochondria function in biogenesis and bioenergetics is also supported and up-regulated by cysteine persulfide derived from mitochondrial CARS (also known as CARS2). Here, we provide an overview of recent advances in reactive persulfide research and our understanding of the mechanisms underlying the formation and the physiological roles of reactive persufides, with a primary focus on the formation of cysteine persulfide by CARS and the most fundamental mitochondrial bioenergetics mediated by persulfides, that is, sulfur respiration.

Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides

“…Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSS n H, n > 1) are cysteine derivatives that have sulfane sulfur atoms that are bound to cysteine thiol [ 1 , 2 , 3 , 4 ]. Various forms of persulfides/polysulfides exist in both prokaryotes and eukaryotes as low-molecular-weight compounds, such as CysSSH, homocysteine persulfide, glutathione persulfide (GSSH), glutathione trisulfide (GSSSH), oxidized glutathione trisulfide (GSSSG), bacillithiol persulfide, and coenzyme A persulfide, and as CysSSHs in proteins ( Figure 1 ) [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

“…CaMK I is activated by phosphorylation at Thr177, which is irreversibly inhibited by Cys177 persulfhydration [ 17 , 18 ]. Recent studies reported that CysSSH can participate in energy metabolism as it functions in sulfur respiration in mitochondria [ 3 , 4 , 6 ]. CysSSH produced by mitochondria-localized cysteinyl-tRNA synthetase is reduced in the presence of mitochondrial electron transfer chain activity to form hydrogen sulfide (H 2 S) [ 6 ].…”

Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells

“…Therefore, the CPERS activity of CysRS is a new function of ARSs beyond translation, which is, in fact, the major pathway for production of endogenous reactive persulfides that is observed in many organisms. In the context of this unique persulfide function, we recently found that cysteine persulfides produced by CysRS in mitochondria can support and up-regulate mitochondrial biogenesis and bioenergetics in eukaryotes (9,10). Therefore, mitochondrial transport and localization of CysRS are presumably crucial steps for energy metabolism in addition to translation in mitochondria, although this view is still hypothetical and needs to be verified.…”

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism

“…A fall in oxygen can also increase H 2 S via other mechanisms. There is a large store of polysulfides in cells [13][14][15][16][17]. A fall in oxygen will increase the reducing environment in cells and reductants such as ascorbate and thioredoxin can then release H 2 S from polysulfides and thiosulfate [18][19][20][21].…”