Melatonin Inhibits mTOR-Dependent Autophagy during Liver Ischemia/Reperfusion

Abstract

Background: Autophagy is a self-digestion system responsible for maintaining cellular homeostasis and interacts with reactive oxygen species produced during ischemia/reperfusion (I/R). Melatonin (MLT) is a potent and endogenous anti-oxidant that has beneficial effects in liver I/R injury. In this study, we examined the cytoprotective mechanisms of MLT in liver I/R, focusing on autophagic flux and associated signaling pathways. Methods: Male C57BL/6 mice were subjected to 70% liver ischemia for 60 min followed by reperfusion. MLT (10 mg/kg, i.p.) was injected 15 min prior to ischemia and again immediately before reperfusion. Rapamycin (Rapa, 1 mg/kg, i.p.), which induces autophagy, was injected 1.5 h before ischemia. Results: Liver I/R increased autophagic flux as indicated by the accumulation of LC3-II and degradation of sequestosome1/p62. This increase was attenuated by MLT. Likewise, electron microscopic analysis showed that autophagic vacuoles were increased in livers of mice exposed to I/R, which was attenuated by MLT. I/R decreased phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 and 70S6K, downstream molecules of the mTOR pathway, but increased expression of calpain 1 and calpain 2. MLT attenuated the decrease in mTOR, 4E-BP1 and 70S6K phosphorylation. Pretreatment of Rapa reversed the effect of MLT on autophagic flux as well as mTOR pathway. Conclusion: Our findings suggest that MLT downregulates autophagy via activation of mTOR signaling, which may in turn contribute to its protective effects in liver I/R injury.

Inhibition of microRNA-101 attenuates hypoxia/reoxygenation-induced apoptosis through induction of autophagy in H9c2 cardiomyocytes

“…As low levels of autophagy during ischemia and early reperfusion protect against cell death, it was suggested that spontaneous upregulation of autophagy may prevent excessive apoptosis of cardiomyocytes in response to H/R. Numerous studies have also demonstrated that autophagy is a beneficial response to ischemia/reperfusion (I/R) (21)(22)(23)(24). For example, increased autophagy was demonstrated to correlate with the functional recovery of the myocardium following I/R, and cardiac myocytes exhibiting enhanced levels of autophagy were found to be negative for apoptosis (25,26).…”

Melatonin Induces Anti-Inflammatory Effects to Play a Protective Role via Endoplasmic Reticulum Stress in Acute Pancreatitis

“…MLT is considered as a type of compound with a clinical application because of its biological functions such as improving sleep, anti-aging, regulating immunity, anti-tumor, and others [17][18][19]. Moreover, MLT inhibits mTOR-dependent autophagy in liver ischemia/reperfusion and protects the esophageal epithelial barrier through ERK1/2 signal transduction [20,21]. In addition, MLT also has anti-oxidant and anti-inflammatory effects.…”

Mitochondrial catastrophe during doxorubicin‐induced cardiotoxicity: a review of the protective role of melatonin

“…Only recently Kang et al [158] demonstrated, using a model of liver ischemia/reperfusion (I/R) injury, that autophagic flux was increased in response to I/ R injury, but this was attenuated by melatonin via inhibiting mammalian target of rapamycin (mTOR)-dependent autophagy [158]. However, it is unclear to what extent melatonin activates mTOR-dependent or mTOR-independent pathways.…”

“…However, it is unclear to what extent melatonin activates mTOR-dependent or mTOR-independent pathways. The suppression of autophagy by melatonin suggested its protective role during I/R injury [158]. It seems possible that melatonin could also potentially suppress the increase in autophagic flux observed during DXR-induced cardiotoxicity; however, this aspect would have to be investigated.…”