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Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation

ABSTRACT: Ergothioneine (ET), a dietary thione/thiol, is receiving growing attention for its possible benefits in healthy aging and metabolic resilience. Our study investigates ET's effects on healthspan in aged animals, revealing extension of lifespan and enhanced mobility in Caenorhabditis elegans, accompanied by improved stress resistance and reduced age-associated biomarkers. In aged rats, ET administration enhances exercise endurance, muscle mass, and vascularization, concomitant with higher NAD+ levels in muscle. Mechanistically, ET acts as an alternative substrate for cystathionine gamma lyase (CSE), stimulating H2S production, which increases protein persulfidation of more than 300 protein targets. Among these, protein persulfidation-driven activation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) primarily contributes to the ET-induced NAD+ increase. ET’s effects are abolished in models lacking CSE and cGPDH, highlighting essential role of H2S signaling and protein persulfidation. These findings elucidate ET's multifaceted actions and provide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.

INSTRUMENT(S): Orbitrap Eclipse, timsTOF Pro 2

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Dunja Petrovic

LAB HEAD: Milos Filipovic

PROVIDER: PXD051587 | Pride | 2025-01-21

REPOSITORIES: pride

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			Action	DRS
	Eclipse_04086_PSSH_D10_Vehicle1.raw	Raw
	Eclipse_04086_PSSH_D10_Vehicle1.raw.refined.mgf	Mgf
	Eclipse_04087_PSSH_D10_ET1.raw	Raw
	Eclipse_04087_PSSH_D10_ET1.raw.refined.mgf	Mgf
	Eclipse_04088_PSSH_D10_Vehicle3.raw	Raw

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Project description:Hydrogen sulfide is an important signaling molecule in plants that regulates essential biological processes through protein persulfidation. Although numerous persulfidated proteins were found to be involved in photorespiration, little was known about sulfide-mediated regulation of photorespiration. Label-free quantitative proteomic analysis has revealed a high impact on the protein persulfidation level when plants grown under non-photorespiratory conditions are transferred to air, with the 97 % of total identified proteins more persulfidated under suppressed photorespiration. A detailed study of the effect of sulfide on important aspects associated with photorespiratory growth conditions has provided insight into the role of sulfide in protecting plants grown under suppressed photorespiration. In these conditions, sulfide amends the metabolic imbalance of carbon/nitrogen and restores ATP levels to concentrations similar to those in air grown conditions. Sulfide also plays an essential role in balancing the significant high level of ROS measured in plants under non-photorespiratory conditions to reach a similar cellular redox state in air-grown plants, through the regulation of antioxidative defenses. Furthermore, sulfide regulates another important characteristic resulting from suppression of photorespiration, such as the stomata closure, to decrease the high guard cell ROS levels and inducing the stomata aperture. In this way, sulfide signals the movement of the CO2-dependent stomata to achieve a scenario similar to that of plants growing under normal air conditions, in the opposite direction of the already established ABA-dependent movement of the stomata. Therefore, our findings suggest that the high persulfidation level under suppressed photorespiration reveals an essential role of sulfide signaling under these conditions, and with respect to stomatal movement, the outcome of this signaling is dependent on the growth/stress condition under study.

Project description:Hydrogen sulfide (H2S) is a signaling molecule that regulates essential plant processes, such as autophagy and responses to abiotic stresses. Although there is much information about the processes in which H2S is involved, the mechanism of action of H2S is still unclear. However, the posttranslational modification of cysteine residues, named persulfidation, is the main proposed mechanism. In this study, the role of H2S during drought that allows plant stress adaptation has been analyzed, with the focus on the underlying mechanism. H2S pretreatment before imposing drought on plants significantly improved phenotypic traits and decreased the content of biochemical and molecular drought stress markers. In addition, H2S regulated amino acid metabolism and repressed drought-induced degradation pathways, such as bulk autophagy and protein ubiquitination. The label-free quantitative proteomic analysis of plants growing under control and drought stress identified 887 proteins significantly different persulfidated between both conditions. Bioinformatic analyses revealed that the biological processes most enriched containing the proteins more persulfidated in drought corresponded to cellular response to oxidative stress, and hydrogen peroxide catabolism. In addition, protein degradation, abiotic stress responses, anthocyanin-containing compound biosynthetic process, and flavonoid biosynthesis were highlighted. On the contrary, the most enriched biological process containing proteins with lower levels of persulfidation in drought corresponded to the biosynthetic processes of glucosinolates and chlorophyll. Therefore, our findings emphasize the role of H2S as a promoter of enhanced tolerance to drought, enabling plants to respond more rapidly and efficiently after exposure to drought. Furthermore, the proteomic analysis supports the main role of protein persulfidation as the molecular mechanism of H2S to alleviate ROS accumulation and balance redox homeostasis under drought stress.

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Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation

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