Disruption of De Novo Serine Synthesis in Müller Cells Induced Mitochondrial Dysfunction and Aggravated Oxidative Damage
| العنوان: | Disruption of De Novo Serine Synthesis in Müller Cells Induced Mitochondrial Dysfunction and Aggravated Oxidative Damage |
|---|---|
| المؤلفون: | Ling Zhu, Mark C Gillies, Michelle Yam, Ting Zhang, Weiyong Shen, Ulrike Grünert, Jianhai Du, Michele C. Madigan, Fanfan Zhou |
| المصدر: | Molecular Neurobiology. 55:7025-7037 |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Ependymoglial Cells, Neuroscience (miscellaneous), HSP72 Heat-Shock Proteins, medicine.disease_cause, Serine, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Adenosine Triphosphate, Lactate dehydrogenase, medicine, Humans, Phosphoglycerate Dehydrogenase, Aged, chemistry.chemical_classification, Reactive oxygen species, Chemistry, Chaperonin 60, Glutathione, Middle Aged, Mitochondria, Up-Regulation, Cell biology, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, Neurology, Glycine, HSP60, Reactive Oxygen Species, Muller glia, NADP, Oxidative stress |
| الوصف: | De novo serine synthesis plays important roles in normal mitochondrial function and cellular anti-oxidative capacity. It is reported to be mainly activated in glial cells of the central nervous system, but its role in retinal Muller glia remains unclear. In this study, we inhibited de novo serine synthesis using CBR-5884, a specific inhibitor of phosphoglycerate dehydrogenase (PHGDH, a rate limiting enzyme in de novo serine metabolism) in MIO-M1 cells (immortalized human Muller cells) and huPMCs (human primary Muller cells) under mild oxidative stress. Alamar blue and LDH (lactate dehydrogenase) assays showed significantly reduced metabolic activities and increased cellular damage of Muller cells, when exposed to CBR-5884 accompanied by mild oxidative stress; however, CBR-5884 alone had little effect. The increased cellular damage was partially reversed by supplementation with exogenous serine/glycine. HSP72 (an oxidative stress marker) and reactive oxygen species (ROS) levels were significantly increased; glutathione and NADPH/NADP+ levels were pronouncedly reduced under PHGDH inhibition accompanied by oxidative stress. JC-1 staining and Seahorse respiration experiments showed that inhibition of de novo serine synthesis in Muller cells can also increase mitochondrial stress and decrease mitochondrial ATP production. qPCR and Western blot demonstrated an increased expression of HSP60 (a key mitochondrial stress-related gene), and this was further validated in human retinal explants. Our study suggests that de novo serine synthesis is important for Muller cell survival, particularly when they are exposed to mild oxidative stress, possibly by maintaining mitochondrial function and generating glutathione and NADPH to counteract ROS. |
| تدمد: | 1559-1182 0893-7648 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2345a33c0e13c17499acd01f9f0fa10cTest https://doi.org/10.1007/s12035-017-0840-8Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....2345a33c0e13c17499acd01f9f0fa10c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15591182 08937648 |
|---|