Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Abstract

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein sulfhydration (R-SSnH). Despite the known importance of sulfhydration on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and boosts endogenous H2S production, expands functional tissue-specific sulfhydromes. Here, we found that 50% DR enriched total sulfhydrated proteins in liver, kidney, muscle, and brain but decreased these in heart of adult male mice. DR promoted sulfhydration in numerous metabolic and aging-related pathways. Mice lacking the H2S producing enzyme cystathionine {gamma}-lyase (CGL) had decreased liver and kidney protein sulfhydration and failed to functionally augment their sulfhydrome in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health. One Sentence SummaryDietary restriction altered the tissue-specific enrichment of sulfhydrated proteins and their downstream signaling pathways in liver, kidney, skeletal muscle, brain, heart, and plasma that was partly dependent on the hydrogen sulfide producing enzyme cystathionine {gamma}-lyase.