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Nat Commun. 2017 Oct 27;8(1):1177. doi: 10.1038/s41467-017-01311-y.

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics.

Author information

1
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan. takaike@med.tohoku.ac.jp.
2
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
3
Department of Molecular Physiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
4
Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.
5
Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
6
Environmental Biology Section, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
7
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
8
Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Osaka, 599-8531, Japan.
9
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
10
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, 980-8577, Japan.
11
Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, 981-1293, Japan.
12
Laboratory of Pharmacology, Showa Pharmaceutical University, Tokyo, 194-8543, Japan.
13
Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan.
14
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, 1122, Hungary.
15
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton, SO16 6YD, UK.
16
Department of Chemistry, Sonoma State University, Rohnert Park, CA, 94928, USA.

Abstract

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.

PMID:
29079736
PMCID:
PMC5660078
DOI:
10.1038/s41467-017-01311-y
[Indexed for MEDLINE]
Free PMC Article

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