Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine \u03b3-lyase-dependent manner

Nazmin Bithi,Belinda Willard,Christopher Link,Jie Yang,Suzie Kim,Rui Wang,Ling Li,Yoko O Henderson,Christopher Hine

doi:10.1038/s41467-021-22001-w

Nazmin Bithi, Belinda Willard + Show 7 more

Open Access

https://doi.org/10.1038/s41467-021-22001-w

Copy DOI

Abstract

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

Highlights

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH)
In the 50% caloric restriction scenario, we examined for diet, tissue, and genotypespecific changes in H2S production (i), protein persulfidation (ii), and biological pathways impacted by persulfidation (iii) (Fig. 1a)
Ad libitum (AL) fed mice were provided 24-h access to food and the 50% dietary restriction (DR) (DR) mice were fed their calculated allotment near the start of their dark phase at 7 pm to avoid disturbances in circadian

Summary

Introduction

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. A common molecular phenomenon amongst several dietary and endocrine models of longevity is the altered metabolism of sulfur-containing amino acids methionine and cysteine, which entails flux through transsulfuration[13,14,15] and increased production capacity and/or bioavailability of hydrogen sulfide (H2S) gas[16]. Increased CGL expression in the liver is a hallmark of numerous dietary, genetic, hormonal, and pharmaceutical models of an extended lifespan and may serve as a molecular biomarker associated with longevity[38]. While the benefits of a diffusible antioxidant to counter oxidative damage along with improvement in bioenergetics to delay the onset of aging-related disorders are identifiable, the act of persulfidation and its extent to improve fitness and lifespan is less understood

Methods

Results

Conclusion