Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during
Chongxi Fan1,2, Jianyu Feng3, Chi Tang4
1Department of Military Biomedical Engineering, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, China. fcx329@fmmu.edu.com.
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.
Insights
Melatonin protects bone marrow mesenchymal stem cells (BMSCs) from oxidative stress by regulating the AMPK-ER stress pathway, enhancing cell survival and mitochondrial function. This study reveals a new therapeutic mechanism for oxidative stress-induced apoptosis in BMSCs.
Area of Science:
- Cell Biology
- Biochemistry
- Stem Cell Research
Background:
- Bone marrow mesenchymal stem cells (BMSCs) are crucial for clinical applications.
- Oxidative stress-induced apoptosis leads to low survival rates in transplanted BMSCs.
- Mechanisms underlying BMSC apoptosis under oxidative stress, particularly involving endoplasmic reticulum (ER) and mitochondria, are not fully understood.
Purpose of the Study:
- To investigate the protective effects of melatonin against oxidative stress in BMSCs.
- To explore the role of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and ER stress pathways in melatonin's cytoprotective mechanism.
- To determine if melatonin relieves ER stress-mediated mitochondrial dysfunction via AMPK.
Main Methods:
- Mouse BMSCs were exposed to hydrogen peroxide (H₂O₂) with or without melatonin.
- Cell damage, oxidative stress, mitochondrial function, AMPK activity, ER stress markers, and apoptosis were assessed.
- Pharmacological agonists and inhibitors of AMPK and ER stress were used to elucidate melatonin's mechanism.
Main Results:
- Melatonin significantly improved BMSC survival and restored mitochondrial function.
- Melatonin modulated AMPK phosphorylation and ER stress pathway molecules.
- AMPK activation and ER stress inhibition by melatonin enhanced mitochondrial membrane potential, reduced oxidative damage, and suppressed apoptosis.
Conclusions:
- Melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis.
- The protective mechanism involves the regulation of the AMPK-ER stress pathway.
- This finding suggests a potential therapeutic strategy for improving BMSC transplantation outcomes.
More Related Videos
10:50Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
12:02Human Primary Trophoblast Cell Culture Model to Study the Protective Effects of Melatonin Against Hypoxia/reoxygenation-induced Disruption
Published on: July 30, 2016
Related Concept Videos
01:07MAPK Signaling Cascades
01:31The Intrinsic Apoptotic Pathway
01:31Regulation of the Unfolded Protein Response
01:22PI3K/mTOR/AKT Signaling Pathway
02:23Abnormal Proliferation