SQR mediates therapeutic effects of H₂S by targeting mitochondrial electron transport to induce mitochondrial...

Hydrogen sulfide (H₂S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H₂S. Therefore, SQR is assumed to inhibit H₂S signaling. We now report that SQR-mediated oxidation of H₂S drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate-activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H₂S. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H₂S following intracerebral hemorrhage. To conclude, SQR mediates H₂S signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications.