Hydrogen sulfide dynamically upregulates copper uptake and localization

The reactivity of copper, an essential micronutrient that undergoes facile cycling between Cu ¹⁺ and Cu ²⁺ redox states, is carefully controlled within the confines of protein binding sites, and by sequestration in storage vesicles, or harnessed to kill pathogens by active pumping of Cu ¹⁺ into phagosomes. We have discovered that hydrogen sulfide, a signaling metabolite generated in copious quantities at the host-microbiome interface, upregulates Cu accumulation in diffusely dispersed puncta across the cell, as visualized by X-ray fluorescence microscopy. The Cu is predominantly in the Cu ²⁺ state with oxygen/nitrogen ligands. Cu import occurs via the non- canonical ZNT1 transporter, while export, following sulfide withdrawal, is ATP7A-dependent. Cu accumulates at the apices of colon crypts in a mouse model of elevated sulfide exposure due to SQOR deficiency in the intestinal epithelium, establishing in vivo relevance. Our study reveals that sulfide is a dynamic regulator of the Cu pool, stimulating Cu ²⁺ influx into highly concentrated puncta.