Melatonin inhibits endometriosis development by disrupting mitochondrial function and regulating tiRNAs

Abstract

Endometriosis is a benign gynecological disease characterized by abnormal growth of endometrial-like cells outside the uterus. Melatonin, a hormone secreted by the pineal gland, has been shown to have therapeutic effects in various diseases, including endometriosis. However, the underlying molecular mechanisms are yet to be elucidated. The results of this study demonstrated that melatonin and dienogest administration effectively reduced surgically induced endometriotic lesions in a mouse model. Melatonin suppressed proliferation, induced apoptosis, and dysregulated calcium homeostasis in endometriotic cells and primary endometriotic stromal cells. Melatonin also caused mitochondrial dysfunction by permeating through the mitochondrial membrane to disrupt redox homeostasis in the endometriotic epithelial and stromal cells. Furthermore, melatonin affected oxidative phosphorylation systems to decrease ATP production in End1/E6E7 and VK2/E6E7 cells. This was achieved through messenger RNA-mediated downregulation of respiratory complex subunits. Melatonin inhibited the PI3K/AKT and ERK1/2 pathways and the mitochondria-associated membrane axis and further suppressed the migration of endometriotic epithelial and stromal cells.Furthermore, we demonstrated that tiRNA GluCTC and tiRNA AspGTC were associated with the proliferation of endometriosis and that melatonin suppressed the expression of these tiRNAs in primary endometriotic stromal cells and lesions in a mouse model. Thus, melatonin can be used as a novel therapeutic agent to manage endometriosis.

Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

“…The modulation of the PI3K/AKT/ mTOR pathway may be influenced by factors such as Ca 2+ transfer, ER stress, and mitochondrial function, all of which are closely associated with MAMs, highlighting the potential role of MAMs. [55][56][57] Therefore, we speculated that post-CIRI MAMs might mediate oxi-…”

Alpinumisoflavone Activates Disruption of Calcium Homeostasis, Mitochondria and Autophagosome to Suppress Development of Endometriosis

“…End1/E6E7 and VK2/E6E7 cells were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA). The detailed information about cell maintenance and culture medium have been described in our previous study [2]. The normal uterine epithelial cells were cultured in ReproLife TM reproductive medium (Lifeline Cell Technology; Frederick, MD, USA) in accordance with the instructions and incubated at 37 °C in a 5% CO 2 incubator.…”

“…The bromo-2 -deoxyuridine (BrdU) ELISA kit (Cat No. : 11647229001, Roche, Basel, Switzerland) was used to assess the proliferative capacity of End1/E6E7 and VK2/E6E7 cells in accordance with the instructions [2,9]. Briefly, End1/E6E7 and VK2/E6E7 cells treated with alpinumisoflavone in a dose-dependent manner (0, 20, and 50 µM) for 48 h were incubated with 10 µM of BrdU.…”

“…The results were examined with flow cytometry and this assay was performed independently in triplicate. The detailed process has been described in our previous studies [2,9].…”

“…It is a disease characterized by the presence of abnormal endometrium-like tissue outside of the female reproductive tract. Some of the associated clinical symptoms are bowel dysfunction, pelvic pain, infertility, absence of menses, and dysmenorrhea, which result in decreased quality of life of the patient [2,3]. In addition, diagnosis of endometriosis is difficult, and its prevalence is increasing in females of reproductive age [4].…”