Human mitochondrial persulfide dioxygenase is potently and reversibly inhibited by nitric oxide.

Hydrogen sulfide (H2S) regulates multiple human physiological processes, its reactivity and range of action being tightly controlled through regulation of H2S-synthesizing and -detoxifying enzymes. H2S detoxification is mainly achieved by a mitochondrial sulfide detoxifying pathway including persulfide dioxygenase (PDO). Human PDO (known as ethylmalonic encephalopathy protein 1, ETHE1), a homodimeric enzyme with a mononuclear iron centre active site, catalyzes the conversion of glutathione persulfide (GSSH) and O2 to reduced glutathione (GSH) and sulfite. Here we report that ETHE1 is potently inhibited by authentic nitric oxide (NO) gas at physiological concentrations, as observed by high resolution respirometry. Inhibition is reversible, occurs via NO binding to the reduced mononuclear iron center and becomes more potent and persistent at lower O2 levels. Incubation with s-nitrosoglutathione (GSNO) also appears to partially and transiently inhibit ETHE1, this effect likely resulting from s-nitrosation of cysteine residues. While ETHE1 is devoid of NO reductase activity, in aerobic conditions it displays low NO degrading activity. These findings unravel a novel layer of cross-regulation between the H2S and NO gasotransmitters with possible implications on the regulation of numerous physiological and pathophysiological processes.