Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Abstract

Aims: Mitochondrion is considered as the major source of intracellular reactive oxygen species (ROS). H 2 S has been reported to be an antioxidant, but its mechanism remains largely elusive. P66Shc is an upstream activator of mitochondrial redox signaling. The aim of this study was to explore whether the antioxidant effect of H 2 S is mediated by p66Shc. Results: Application of exogenous H 2 S with its donor, NaHS, or overexpression of its generating enzyme, cystathionine b-synthase, induced sulfhydration of p66Shc, but inhibited its phosphorylation caused by H 2 O 2 /D-galactose in SH-SY5Y cells or in the mice cortex. H 2 S also decreased mitochondrial ROS production and protected neuronal cells against stress-induced senescence. PKC bII and PP2A are the two key proteins to regulate p66Shc phosphorylation. Although H 2 S failed to affect the activities of these two proteins, it disrupted their association. Cysteine-59 resides in proximity to serine-36, the phosphorylation site of p66Shc. The C59S mutant attenuated the above-described biological function of H 2 S. Innovation: We revealed a novel mechanism for the antioxidant effect of H 2 S and its role in oxidative stress-related diseases. Conclusion: H 2 S inhibits mitochondrial ROS production via the sulfhydration of Cys-59 residue, which in turn, prevents the phosphorylation of p66Shc. Antioxid. Redox Signal. 21, 2531-2542.

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

“…Another study demonstrates that the capacity of H 2 S to protect against oxidative stress is executed via persulfidation (25,26). These findings together with our results suggest that boosting the transsulfuration pathway may contribute to neuroprotection via increased persulfidation of proteins.…”

“…After addition of sodium hydrogen sulfide and L-cysteine, levels of protein persulfidation (also called protein S-sulfhydration) increased in a CSE-dependent manner in vitro (23), suggesting an influential effect of this type of posttranslational protein modification. Indeed, protein persulfidation has been demonstrated to mediate the activity of parkin, to serve as an antioxidant and to protect against cellular senescence (24)(25)(26). A possible link between SCA3, CSE and protein persulfidation remains to be determined as well as the potential neuroprotective effects of overexpressing the CSE enzyme directly in a neurodegenerative background.…”

Persulfidation (S-sulfhydration) and H2S

“…P66Shc À/À mice show 30 % increase of the lifespan. It has been shown recently that sulfhydration of p66Shc impaired the association of PKC βII and p66Shc and attenuated H 2 O 2 -induced p66Shc phosphorylation, a critical step in p66Shc-mediated mitochondrial ROS generation (Xie et al 2014). H 2 S is known to have dramatic effects on inhibiting oxidative stress, something that cannot be simply explained by its direct redox chemistry.…”

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

“…It has been found to play a role in several (patho)physiological processes. The downstream effects of sulfhydration include anti-inflammatory and antiapoptotic actions of nuclear factor kappa B (NF-κB), regulation of endoplasmic reticulum stress responses through protein tyrosine phosphatase 1B, vasodilation by the opening of ATP-sensitive K + (KATP) channels, suppression of cellular senescence through 8-nitroguanosine-3′,5′-cyclic monophosphate and Kelch-like ECH-associated protein 1, and anti-oxidant actions of mitochondrial redox signaling activator p66Shc [27,[32][33][34][35][36][37]. H2S treatment to modulate sulfhydration seems to be eligible for various pathological conditions.…”