Melatonin: A Cosmic Shield Against Liver Dysfunction in Zero Gravity

Melatonin is a hormone produced by the pineal gland in the brain, primarily in response to darkness. It plays a crucial role in regulating the sleep-wake cycle, or circadian rhythm, helping to control the timing of when sleep occurs. The production and release of melatonin are influenced by the body’s internal clock and environmental light conditions, with levels typically rising in the evening to promote sleep and decreasing in the morning to help wakefulness. Microgravity, a condition experienced during spaceflight, has been documented to induce various physiological alterations in humans, including muscle atrophy, bone density loss, and cardiovascular deconditioning. Among these, the liver’s response to microgravity is of significant interest due to its central role in metabolism and detoxification. The liver’s multifunctionality makes it susceptible to environmental changes, including alterations in gravitational forces. There have been various studies and experiments conducted on the International Space Station and other space missions to understand better and mitigate the effects of microgravity on human physiology, including sleep and melatonin production. These studies often involve monitoring astronauts’ sleep patterns, melatonin levels, and exposure to artificial light sources designed to mimic a natural day-night cycle, helping to regulate circadian rhythms and improve sleep quality in a microgravity environment.

A new study published in FASEB Journal by Yue Xiong, Chiyuan Ma, Qin Li, Wenya Zhang, Huashan Zhao, Peigen Ren, Ke Zhang and Associate Professor Xiaohua Lei from the Shenzhen Institute of Advanced Technology- Chinese Academy of Sciences, conducted a study to understand the effects of simulated microgravity (SMG) on hepatocytes, focusing on mitochondrial dysfunction and lipid metabolism dysregulation. They employed a random positioning machine to create an environment mimicking the microgravity conditions experienced in space to study its impact on liver cells in vitro. These studies enhance our understanding on molecular mechanisms underpinning the adverse effects of microgravity on liver cells and evaluates the potential therapeutic application of melatonin in counteracting these deleterious consequences.

The researchers used a random positioning machine to simulate the microgravity conditions. This device allows for the constant reorientation of cells, effectively nullifying the net gravitational pull experienced by the cells, thus simulating the microgravity conditions of space. They cultured human and mouse hepatocyte cell lines under normal gravity (NG) conditions initially and then exposed to SMG to study the effects of microgravity. Some of the cells were treated with melatonin to assess its potential protective effects against SMG-induced changes.

The team evaluated cell viability, cell cycle progression, and apoptosis rates in hepatocytes exposed to SMG, using various assays including cell counting kit-8 (CCK-8), flow cytometry for cell cycle analysis, and annexin V/PI staining for apoptosis detection. Lipid accumulation within the hepatocytes was visually assessed using Oil Red O staining, and quantitatively measured by determining intracellular triglyceride levels.

The researchers examined mitochondrial function through several approaches, including JC-1 dye staining to assess mitochondrial membrane potential, MitoTracker Green staining for mitochondrial distribution, and Seahorse assays to measure oxygen consumption rates indicative of mitochondrial respiration. They performed RNA sequencing on hepatocytes to identify differentially expressed genes under SMG conditions, with a particular focus on genes involved in lipid metabolism and mitochondrial function. To test the therapeutic potential of melatonin, some hepatocyte cultures were treated with this antioxidant under SMG conditions to observe any mitigating effects on the observed cellular dysfunctions.

The authors showed that SMG led to decreased hepatocyte viability, induced cell cycle arrest, and increased apoptosis rates compared to cells maintained under normal gravity. Moreover, there was a significant accumulation of lipids and elevation of triglyceride levels in hepatocytes exposed to SMG, indicating disrupted lipid metabolism. Furthermore, hepatocytes under SMG showed signs of mitochondrial dysfunction, including decreased mitochondrial membrane potential, altered mitochondrial distribution, and impaired mitochondrial respiration.  A noteworthy aspect of this study is the comprehensive analysis of gene expression alterations under SMG conditions. RNA sequencing data illuminate the upregulation of genes involved in lipid metabolism pathways, including PPARγ, CD36, and various fatty acid binding proteins (FABPs), which are implicated in the accumulation of lipids within hepatocytes. This genetic reprogramming underlines the profound impact of SMG on hepatocyte metabolic functions.

The study’s innovation lies in the examination of melatonin’s protective role against SMG-induced hepatocyte dysfunction. Melatonin, a well-known antioxidant produced by the pineal gland, demonstrates remarkable efficacy in ameliorating the adverse effects of SMG. The administration of melatonin not only restores hepatocyte viability and mitigates lipid accumulation but also normalizes mitochondrial function. The antioxidant properties of melatonin reduce ROS levels, thereby protecting mitochondria from oxidative stress and preserving their function. The mechanistic insights provided by this research are substantial. The study elucidates a pathophysiologic feedback loop where mitochondrial dysfunction and lipid metabolism dysregulation mutually reinforce each other under microgravity conditions. This vicious cycle highlights the interconnectedness of cellular metabolic processes and the profound impact environmental factors like gravity can have on them. Furthermore, the study explores the potential of melatonin as a therapeutic agent for protecting liver function in environments of altered gravity, such as spaceflight. The findings suggest that melatonin could be a valuable addition to countermeasures aimed at preserving astronaut health during prolonged space missions.

In conclusion, the authors comprehensively demonstrated the detrimental effects of simulated microgravity on hepatocyte function, highlighting mitochondrial dysfunction and lipid metabolism dysregulation as key concerns. Importantly, it also presents melatonin as a potential protective agent against these microgravity-induced cellular dysfunctions, offering valuable insights for safeguarding astronaut health during space missions and providing implications for liver disease research on Earth.