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Hydrogen sulfide dynamically upregulates copper uptake and localization

Diessl, J.; Roman, J.; Kumar, R.; Hanna, D. A.; Sue, A.; Crawford, A.; Shokohi, R.; Parikh, A.; Pattammattel, A.; Kiss, A.; Zhao, K.; Larkin, A.; Fu, Y.; Guo, A.; Durham, T.; Antoniewicz, M. R.; Chen, S.; Gohil, V.; Mootha, V.; Shah, Y.; Reddi, A. R.; Ragunathan, K.; Sarangi, R.; O'Halloran, T. V.; Ralle, M.; Banerjee, R.

2026-07-31 cell biology
10.64898/2026.07.30.741779 bioRxiv
Show abstract

The reactivity of copper, an essential micronutrient that undergoes facile cycling between Cu1+ and Cu2+ 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 Cu1+ 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 Cu2+ 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 Cu2+ influx into highly concentrated puncta.

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