Edited by Noboru MizushimaKeywords: Mitophagy UNC-51 like kinase Adenosine 5 0 -monophosphate (AMP)-activated protein kinase Hypoxia Autophagy Mitochondria a b s t r a c t UNC-51 like kinase (ULK1) translocates to dysfunctional mitochondria and is involved in mitophagy, but the mechanisms responsible for ULK1 activation and translocation remain unclear. Here, we found that hypoxia induces phosphorylation of ULK1 at Serine-555 by Adenosine 5 0 -monophosphate (AMP)-activated protein kinase (AMPK). Unlike wild-type ULK1, an ULK1 (S555A) mutant cannot translocate to mitochondria in response to hypoxia. Inhibition or knockdown of AMPK prevents ULK1 translocation and inhibits mitophagy. Finally, the phospho-mimic ULK1 (S555D) mutant, but not ULK1 (S555A), rescues mitophagy in AMPK-knockdown cells. Thus, we conclude that AMPK-dependent phosphorylation of ULK1 is critical for translocation of ULK1 to mitochondria and for mitophagy in response to hypoxic stress.

Background: Mitophagy and microRNA both regulate the occurrence of neurodegenerative diseases and cancers. Results: MicroRNA-137, a hypoxia responsive microRNA, inhibits mitophagy via targeting two mitophagy receptors. Conclusion: A novel link between miR-137 and mitophagy has been revealed. Significance: Understanding mitophagy regulation and microRNA functions may provide new concepts to fight human diseases.

IntroductionBased on the previous research that oroxylin A can suppress inflammation, we investigated the hepatoprotective role of oroxylin A against CCl4-induced liver damage in mice and then studied the possible alteration of the activities of cytokine signaling participating in liver regeneration. Wild type (WT) mice were orally administrated with oroxylin A (60 mg/kg) for 4 days after CCl4 injection, the anti-inflammatory effects of oroxylin A were assessed directly by hepatic histology and indirectly by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Albumin. Proliferating cell nuclear antigen (PCNA) staining was performed to evaluate the role of oroxylin A in promoting hepatocyte proliferation. Serum IL-1β, TNF-α, IL-6 and IL-1Ra levels were measured by enzyme-linked immunosorbent assay (ELISA) and liver HGF, EGF, TNF-α, IL-6, IL-1Ra and IL-1β gene expression was determined by quantitative real-time PCR. The data indicated that the IL-6 and TNF-α mRNA of oroxylin A administered group significantly increased higher than the control within 12 hours after CCl4 treatment. Meanwhile, oroxylin A significantly enhanced the expression of IL-1Ra at the early phase, which indicated that oroxylin A could facilitate the initiating events in liver regeneration by increasing IL-1Ra which acts as an Acute-Phase Protein (APP). In addition, a lethal CCl4-induced acute liver failure model offers a survival benefit in oroxylin A treated WT mice. However, oroxylin A could not significantly improve the percent survival of IL-1RI−/− mice with a lethal CCl4-induced acute liver failure.ConclusionsOur study confirmed that oroxylin A could strongly promote liver structural remodeling and functional recovery through IL-1Ra/IL-1RI signaling pathway. All these results support the possibility of oroxylin A being a therapeutic candidate for acute liver injury.

Dihydromyricetin (DHM) is a flavonoid compound which possesses potent antitumor activity. In the present study, it was demonstrated that DHM significantly inhibited proliferation and induced apoptosis in mouse hepatocellular carcinoma Hepal-6 cells. Transforming growth factor β (TGF-β) is recognized as a major profibrogenic cytokine and is therefore a common target for drugs in the treatment of liver disease. The present study aimed to investigate whether TGF-β was involved in DHM-triggered cell-viability inhibition and apoptosis induction. An MTT assay was used to evaluate the viability of Hepal-6 cells following DHM treatment. TGF-β signalling is mediated by Smads and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a crucial regulator of reactive oxygen species ROS production. TGF-β, Smad3, phosphorylated (p)-Smad2/3 and NOX4 protein expression levels were evaluated by western blot analysis. TGF-β and NOX4 gene expression levels were determined by quantitative polymerase chain reaction. The results indicated that DHM downregulated TGF-β, Smad3, p-Smad2/3 and NOX4 in a concentration-dependent manner. A cell counting assay indicated that DHM also inhibited Hepal-6 cell growth in a concentration-dependent manner. TGF-β expression was significantly decreased following DHM treatment. In conclusion, the results of the present study defined and supported a novel function for DHM, indicating that it induced cell apoptosis by downregulating ROS production via the TGF-β/Smad3 signaling pathway in mouse hepatocellular carcinoma Hepal-6 cells.