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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. (Hepatology 2017;66:1989-2001).

Dysfunctions of epithelial–mesenchymal transition (EMT)-regulated cell migration and invasion have been involved in the pathogenesis of pre-eclampsia (PE). However, the role of circRNAs in EMT of PE has not been widely investigated. In this study, we identified that circTNRC18 was upregulated in PE placentas compared with normal pregnancy placentas. Moreover, circTNRC18 negatively regulated trophoblast cell migration and EMT. Overexpression of circTNRC18 reduced while depletion of circTNRC18 enhanced trophoblast cell migration and EMT. Mechanistically, circTNRC18 sponged miR-762 contributed to inhibit miR-762 activity and elevated EMT-related transcriptional factor Grhl2 protein level. miR-762 expression was lower in PE placentas and played a promoting role in trophoblast cell migration and EMT. In contrast, Grhl2 was highly expressed in PE placentas. Furthermore, we confirmed that upregulation of Grhl2 by circ-TNRC18-induced inhibition of miR-762 led to trophoblast cell migration and EMT. In conclusions, circTNRC18/miR-762/Grhl2 axis plays a key role in trophoblast cell migration and EMT. circTNRC18/miR-762/Grhl2 axis may be a potential therapeutic target in PE.

Hepatic ischemic reperfusion injury (IRI) is a common complication of liver surgery. Although an imbalance between mitochondrial fission and fusion has been identified as the cause of IRI, the detailed mechanism remains unclear. Augmenter of liver regeneration (ALR) was reported to prevent mitochondrial fission by inhibiting dynamin-related protein 1 (Drp1) phosphorylation, contributing partially to its liver protection. Apart from phosphorylation, Drp1 activity is also regulated by small ubiquitin-like modification (SUMOylation), which accelerates mitochondrial fission. This study aimed to investigate whether ALR-mediated protection from hepatic IRI might be associated with an effect on Drp1 SUMOylation. Liver tissues were harvested from both humans and from heterozygous ALR knockout mice, which underwent IRI. The SUMOylation and phosphorylation of Drp1 and their modulation by ALR were investigated. Hepatic Drp1 SUMOylation was significantly increased in human transplanted livers and IRI-livers of mice. ALR-transfection significantly decreased Drp1 SUMOylation, attenuated the IRI-induced mitochondrial fission and preserved mitochondrial stability and function. This study showed that the binding of transcription factor Yin Yang-1 (YY1) to its downstream target gene UBA2, a subunit of SUMO-E1 enzyme heterodimer, was critical to control Drp1 SUMOylation. By interacting with YY1, ALR inhibits its nuclear import and dramatically decreases the transcriptional level of UBA2. Consequently, mitochondrial fission was significantly reduced, and mitochondrial function was maintained. This study showed that the regulation of Drp1 SUMOylation by ALR protects mitochondria from fission, rescuing hepatocytes from IRI-induced apoptosis. These new findings provide a potential target for clinical intervention to reduce the effects of IRI during hepatic surgery.