Journal Article Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

Akaike, Takaaki  ,  Ida, Tomoaki  ,  Wei, Fan-Yan  ,  Nishida, Motohiro  ,  Kumagai, Yoshito  ,  Alam, Md. Morshedul  ,  Ihara, Hideshi  ,  Sawa, Tomohiro  ,  Matsunaga, Tetsuro  ,  Kasamatsu, Shingo  ,  Nishimura, Akiyuki  ,  Morita, Masanobu  ,  Tomizawa, Kazuhito  ,  Nishimura, Akira  ,  Watanabe, Satoshi  ,  Inaba, Kenji  ,  Shima, Hiroshi  ,  Tanuma, Nobuhiro  ,  Jung, Minkyung  ,  Fujii, Shigemoto  ,  Watanabe, Yasuo  ,  Ohmuraya, Masaki  ,  Nagy, Péter  ,  Feelisch, Martin  ,  Fukuto, Jon M.  ,  Motohashi, Hozumi

8 ( 1 )  , p.1177 , 2017-10 , Nature
ISSN:2041-1723
NCID:AA12645905
Description
Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. 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 demonstrate effective CysSSH synthesis from the substrate l-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation 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.
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