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

Stem Cell Research & Therapy

Liwen Zhu¹  Lele Feng²  Jianyu Feng²  Hanzhao Zhu²  Weixun Duan²  Zhengbin Zhang³  Chi Tang⁴  Mingming Zhai⁴  Erping Luo⁴  Zedong Yan⁴  Chongxi Fan⁵  Yingtong Feng⁶ 

[1] Department of Cardiology, The First Affiliated Hospital of Xi’an Medical University, 277 Yanta West Road, 710077, Xi’an, China;Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, 127 Changle West Road, 710032, Xi’an, China;Department of Geriatrics, The 8th Medical Center of Chinese PLA General Hospital, 17 Heishanhu Street, 100091, Beijing, China;Department of Military Biomedical Engineering, Air Force Medical University, 169 Changle West Road, 710032, Xi’an, China;Department of Military Biomedical Engineering, Air Force Medical University, 169 Changle West Road, 710032, Xi’an, China;Department of Oncology, Air Force Medical Center of PLA, 30 Fucheng Road, 100142, Beijing, China;Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, 1 Xinsi Road, 710038, Xi’an, China;

关键词: Melatonin;    Bone marrow mesenchymal stem cells;    ER stress;    AMPK;    Oxidative stress;   

DOI  :  10.1186/s13287-020-01948-5

来源: Springer

【 摘 要 】

BackgroundBone 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.MethodsMouse 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.ResultsMelatonin 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.ConclusionsOur 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.

【 授权许可】

CC BY