Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

TLDR

Cysteine hydropersulfide (CysSSH) is abundant in many organisms, yet its biosynthesis and physiological roles remain poorly understood, and persulfide formation is widespread in proteins, likely arising from post‑translational hydrogen‑sulfide chemistry. The study aims to show that cysteinyl‑tRNA synthetases (CARSs) catalyze CysSSH synthesis from cysteine and to explore how CARS‑dependent persulfide production could clarify redox signaling and identify therapeutic targets for oxidative stress and mitochondrial dysfunction. The authors demonstrate that both prokaryotic and mammalian CARS enzymes catalyze the conversion of l‑cysteine into CysSSH. Loss of mitochondrial CARS genes in mice and human cells reduces endogenous CysSSH production, indicating that CARS are the primary.

Abstract

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.