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

Hydrogen sulfide (H₂S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SS_nH). Despite the known importance of persulfidation 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 can boost H₂S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was 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 H₂S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes 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.