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Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics
Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics
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.
Akaike, Takaaki
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Ida, Tomoaki
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Wei, Fan-yan
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Nishida, Motohiro
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Kumagai, Yoshito
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Alam, Md. Morshedul
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Ihara, Hideshi
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Sawa, Tomohiro
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Matsunaga, Tetsuro
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Kasamatsu, Shingo
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Nishimura, Akiyuki
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Morita, Masanobu
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Tomizawa, Kazuhito
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Nishimura, Akira
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Watanabe, Satoshi
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Inaba, Kenji
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Shima, Hiroshi
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Tanuma, Nobuhiro
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Jung, Minkyung
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Fujii, Shigemoto
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Watanabe, Yasuo
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Ohmuraya, Masaki
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Nagy, Péter
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Feelisch, Martin
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Fukuto, Jon M.
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Motohashi, Hozumi
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Akaike, Takaaki
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Ida, Tomoaki
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Wei, Fan-yan
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Nishida, Motohiro
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Kumagai, Yoshito
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Alam, Md. Morshedul
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Ihara, Hideshi
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Sawa, Tomohiro
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Matsunaga, Tetsuro
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Kasamatsu, Shingo
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Nishimura, Akiyuki
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Morita, Masanobu
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Tomizawa, Kazuhito
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Nishimura, Akira
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Watanabe, Satoshi
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Inaba, Kenji
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Shima, Hiroshi
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Tanuma, Nobuhiro
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Jung, Minkyung
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Fujii, Shigemoto
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Watanabe, Yasuo
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Ohmuraya, Masaki
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Nagy, Péter
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Feelisch, Martin
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Fukuto, Jon M.
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Motohashi, Hozumi
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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. and Motohashi, Hozumi (2017) Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics Nature Communications, 8, (1) (doi:10.1038/s41467-017-01311-y).

Record type: Article

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.

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Accepted/In Press date: 29 August 2017
e-pub ahead of print date: 27 October 2017
Published date: 1 December 2017

Identifiers

Local EPrints ID: 415191
URI: http://eprints.soton.ac.uk/id/eprint/415191
PURE UUID: d16804a4-1502-4e12-a368-86b20b43a75a
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 02 Nov 2017 17:30
Last modified: 01 Dec 2017 17:31

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Contributors

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

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