Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acyl-tRNA Synthetases / metabolism*
  • Animals
  • Computer Simulation
  • Cysteine / analogs & derivatives
  • Cysteine / chemistry*
  • Disulfides / chemistry
  • Energy Metabolism*
  • Escherichia coli / metabolism
  • Humans
  • Hydrogen Sulfide / chemistry
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Oxidation-Reduction
  • Protein Processing, Post-Translational
  • Recombinant Proteins / metabolism
  • Sulfhydryl Compounds / chemistry
  • Sulfides / chemistry
  • Tandem Mass Spectrometry

Substances

  • Disulfides
  • Recombinant Proteins
  • Sulfhydryl Compounds
  • Sulfides
  • cysteine persulfide
  • Amino Acyl-tRNA Synthetases
  • cysteinyl-tRNA synthetase
  • Cysteine
  • Hydrogen Sulfide