Hepatic Stimulator Substance Resists Hepatic Ischemia/Reperfusion Injury by Regulating Drp1 Translocation and Activation

Ischemia/reperfusion injury, induced by abnormal mitochondrial fission-related apoptosis, is a major concern in liver transplantation settings. Our previous studies have demonstrated that hepatic stimulator substance (HSS) is an antiapoptotic effector and could protect liver from ischemia/reperfusion injury. However, the underlying mechanism remains unclear. In the present study, we report that in vitro and in vivo HSS could regulate mitochondrial fission and hepatocyte apoptosis during liver ischemia/reperfusion injury by orchestrating the translocation and activation of dynamin-related protein 1 (Drp1). Using a mouse model of ischemia/reperfusion-induced liver injury, we found that HSS-haploinsufficient (HSS+/-) mice displayed exacerbated liver damage based on their increased serum aminotransferase levels, cell structural destruction, and apoptosis levels compared to wild-type (HSS+/+) littermates. Disruption of HSS markedly increased cyclin-dependent kinase 1 (CDK1) and Bax expression, accompanied by elevated phosphorylated Drp1 and release of cytochrome c. In parallel in vitro studies, we found that HSS could inhibit the expression of CDK1 and that HSS inhibits hepatocyte apoptosis through its suppression of CDK1/cyclin B-mediated phosphorylation at Ser-616 of Drp1, thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. On the contrary, knockdown of HSS increased CDK1 as well as Drp1 phosphorylation and aggravated hepatocellular apoptosis. Mechanistic investigation showed that HSS was able to reduce the stability and translation of CDK1 mRNA by modulating the expression of several microRNAs (miRs), including miR-410-3p, miR-490-3p, and miR-582-5p. Conclusion: Our data reveal a novel mechanism for HSS in regulating the mitochondrial fission machinery and further suggest that modulation of HSS may provide a therapeutic approach for combating liver damage.