Thiosulfate protects against hepatic ischemia-reperfusion injury via improving the mitochondrial stress response

Abstract

Objective: Ischemia-reperfusion injury (IRI) complicates revascularization and organ transplantation [1]. Increased reactive oxygen species and subsequent mitochondrial dysfunction induce tissue dysfunction and injury after ischemia-reperfusion [2]. The gasotransmitter hydrogen sulfide (H2S) protects against IRI, but its therapeutic utility remains elusive [3]. We investigated whether sodium thiosulfate (STS) protective in IRI, mimicking the effects of H2S.Methodology: We analysed the effects of STS on mitochondrial respiration and function using an ex vivo isolated liver IRI model and assessed serology, histology, mitophagy markers and electron microscopic changes. We also performed in vivo intravital microscopy.Results: Mice deficient in the endogenous H2S-producing enzyme cystathionine gamma-lyase showed increased mitochondrial dysfunction during hepatic IRI. The fast-releasing H2S donor (NaHS) ameliorated dysfunction but with narrow therapeutic window. In contrast, STS produced similar protective effects but with greater than an order of magnitude broader therapeutic window, while additionally acting as an antioxidant. STS significantly reduced LDH release ex vivo correlating with decreased autophagy and preservation of mitochondrial ultra-structure. Finally, STS protected against tissue injury in vivo by reducing necrosis and decreasing circulating markers of tissue injury.Conclusion: STS, a well-tolerated drug to treat e.g. cyanide poisoning, is a potential drug to treat hepatic IRI.