Melatonin Promotes Mitochondrial Biogenesis and Mitochondrial Degradation in Hepatocytes During Sepsis

Objective center dot This study aimed to investigate the protective mechanisms of melatonin in an in vitro model of sepsisinduced hepatocyte injury, specifically focusing on mitophagy and mitochondrial biogenesis. Methods center dot In this study, we utilized lipopolysaccharide (LPS)-treated AML12 cells to establish an in vitro model of sepsis-induced hepatocyte injury. The effects of melatonin pretreatment were examined through various analyses, including assessments of oxidative stress, inflammation, mitophagy, mitochondrial biogenesis, and adenosine triphosphate (ATP) levels. Results center dot The results revealed that LPS-treated AML12 cells exhibited elevated levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 protein, intracellular reactive oxygen species (ROS), and lipid peroxidation, specifically malondialdehyde (MDA). Moreover, the levels of key markers associated with mitophagy, including PTEN-induced putative kinase 1 (PINK1), parkin, and LC3, were significantly increased (P <.05). Similarly, markers of mitochondrial biogenesis, such as peroxisome proliferatoractivated receptor-gamma coactivator 1 alpha ( PGC-1 alpha), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM), were also significantly increased (P <.05). Conversely, superoxide dismutase (SOD) activity and ATP levels were significantly decreased in LPS-treated AML12 cells compared to the control group (P <.05). However, melatonin pretreatment led to a significant decrease in TNF-alpha and IL-6 protein levels, intracellular ROS, and MDA levels (P <.05), along with a significant increase in SOD activity, ATP levels, and markers of mitophagy and mitochondrial. Conclusions center dot Our findings demonstrate that melatonin plays a role in regulating mitochondrial quality control in sepsis-induced hepatocytes. It achieves this result by promoting mitophagy and inducing mitochondrial biogenesis, thereby selectively eliminating dysfunctional mitochondria.