Melatonin regulates endoplasmic reticulum stress in diverse pathophysiological contexts: A comprehensive mechanistic review.
Luiz Gustavo de Almeida ChuffaFábio Rodrigues Ferreira SeivaHenrique S SilveiraRoberta Carvalho CesárioKarolina da Silva TononVinicius Augusto SimãoDebora Aparecida P C ZuccariRussel J ReiterPublished in: Journal of cellular physiology (2024)
The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin's therapeutic potential in these conditions.
Keyphrases
- oxidative stress
- endoplasmic reticulum stress
- endoplasmic reticulum
- cell death
- induced apoptosis
- clinical trial
- insulin resistance
- diabetic rats
- quality control
- ischemia reperfusion injury
- dna damage
- cell cycle arrest
- estrogen receptor
- metabolic syndrome
- type diabetes
- adipose tissue
- drug delivery
- binding protein
- high fat diet
- protein protein
- small molecule
- risk factors
- squamous cell
- single molecule
- young adults
- polycystic ovary syndrome
- machine learning
- childhood cancer