Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage

Abstract

Background Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. Methods Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. Results Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-l-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. Conclusions Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

Anti-Apoptosis and Autophagy Effects of Melatonin Protect Rat Chondrocytes against Oxidative Stress via Regulation of AMPK/Foxo3 Pathways

“…11 Previous studies demonstrated that AMPK activation restored mitochondrial function by maintaining redox status and sustaining mitochondrial membrane potential, which inhibits mitochondria-induced apoptosis. 12 Downstream transcriptional factors dependent on the AMPK signaling axis, such as Nrf2, Sirt1, and Foxo, regulate several genes that reinforce antioxidant defenses. 13-15 Moreover, senescent cells respond to oxidative stress through mitophagy, which is the process of selectively clearing long-lived or fragmented mitochondria.…”

Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

“…It has been reported that melatonin suppresses ER stress-mediated proapoptotic effects in bone mesenchymal stem cells [29]. Suwanjang W et al suggested that the protective effect of melatonin is mediated via cytosolic calcium in DEX-induced neurotoxicity [30].…”

Therapeutic Effects of Melatonin on Ocular Diseases: Knowledge Map and Perspective

“…However, the role of melatonin in regulating other ocular stem cells, such as corneal epithelial stem cells, and the assessment of their effect in treating ocular diseases in animal models are still unknown. Furthermore, melatonin also exhibits regulating ability for exogenous stem cells such as mesenchymal stem cells (MSCs) in viability, proliferation, differentiation, paracrine, and apoptosis through certain signaling pathways like Wnt and MAPK and acts as antioxidant agents to reduce the oxidative stress–induced apoptosis and enhance activity of stem cells ( Ping et al, 2017 ; Chatterji et al, 2018 ; Lee et al, 2018 ; Majidinia et al, 2018 ; Fan et al, 2020 ; Giannaccare et al, 2020 ). Such properties of melatonin have been successfully applied in various disease therapies, including chronic kidney diseases, neurodegenerative diseases, and orthopedic disorders, through pretreatment or combining with scaffold, while its application is rare for ocular diseases ( Ramezani et al, 2020 ; Yan et al, 2020 ; Yoon et al, 2020 ).…”