Melatonin protects against LPS-induced inflammation and oxidative stress in hepatocytes by enhancing mitophagy and mitochondrial biogenesis

Abstract Background: Melatonin have a protective effect in the liver during sepsis by counteracting oxidative stress and reducing inflammatory responses. Melatonin also regulates mitochondrial biogenesis. This study explored the mechanisms by which melatonin protects against liver injury in experimental sepsis with a focus on mitophagy and mitochondrial biogenesis.Methods and Results: An in vitro model of sepsis-induced hepatocyte injury was established using AML12 cells. Indicators of oxidative stress, inflammation, mitophagy and mitochondrial biogenesis were assessed. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 protein levels, intracellular reactive oxygen species (ROS) levels, lipid peroxidation (malondialdehyde [MDA] levels), and markers of mitophagy (PTEN-induced putative kinase 1 [PINK1] and Parkin) and mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator 1a [PGC-1α], nuclear respiratory factor 1 [NRF-1], mitochondrial transcription factor A [TFAM]) were significantly increased, while superoxide dismutase (SOD) activity and intracellular adenosine triphosphate (ATP) levels were significantly decreased in LPS-treated AML12 cells compared to controls. TNF-α and IL-6 protein levels and intracellular ROS and MDA levels were significantly decreased, while SOD activity, intracellular ATP levels, and markers of mitophagy and mitochondrial biogenesis were significantly increased by melatonin pre-treatment.Conclusion: This study demonstrated that melatonin was involved in the maintenance of mitochondrial homeostasis in hepatocytes during sepsis. Mechanisms involved selective elimination of dysfunctional mitochondria through mitophagy and induction of mitochondrial biogenesis.