M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling
Abstract Neuronal ferroptosis plays a vital role in the progression of neonatal hypoxic-ischemic brain damage (HIBD). M2-type microglia-derived exosomes (M2-exos) have been shown to protect neurons from ischemia–reperfusion (I/R) brain injury, but their impact on I/R-induced neuronal ferroptosis and...
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-03091-8 |
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| author | Jian Li Qing Chen Hao Gu |
| author_facet | Jian Li Qing Chen Hao Gu |
| author_sort | Jian Li |
| collection | DOAJ |
| description | Abstract Neuronal ferroptosis plays a vital role in the progression of neonatal hypoxic-ischemic brain damage (HIBD). M2-type microglia-derived exosomes (M2-exos) have been shown to protect neurons from ischemia–reperfusion (I/R) brain injury, but their impact on I/R-induced neuronal ferroptosis and the underlying mechanisms remain poorly understood. In this study, we used an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT-22 neuronal cells to investigate how M2-exos modulate ferroptosis. We found that M2-exos were internalized by HT-22 cells and significantly attenuated OGD/R-induced ferroptosis. Mechanistically, M2-exos enhanced mitophagy, which was mediated by the upregulation of FUN14 domain-containing protein 1 (FUNDC1), thereby inhibiting ferroptosis. Further analysis revealed that M2-exos activated FUNDC1-dependent mitophagy through the AMP-activated protein kinase (AMPK)/UNC-51-like kinase 1 (ULK1) signaling pathway. Taken together, these findings suggest that M2-exos ameliorate I/R-induced neuronal ferroptosis by enhancing FUNDC1-mediated mitophagy through the activation of AMPK/ULK1 signaling pathway. |
| format | Article |
| id | doaj-art-d600dd09cf994ecbbfbb20ff26f10ec3 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-d600dd09cf994ecbbfbb20ff26f10ec32025-08-20T01:53:11ZengNature PortfolioScientific Reports2045-23222025-05-0115111110.1038/s41598-025-03091-8M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signalingJian Li0Qing Chen1Hao Gu2Department of Anesthesiology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical UniversityDepartment of Anesthesiology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical UniversityDepartment of Pediatrics, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical UniversityAbstract Neuronal ferroptosis plays a vital role in the progression of neonatal hypoxic-ischemic brain damage (HIBD). M2-type microglia-derived exosomes (M2-exos) have been shown to protect neurons from ischemia–reperfusion (I/R) brain injury, but their impact on I/R-induced neuronal ferroptosis and the underlying mechanisms remain poorly understood. In this study, we used an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT-22 neuronal cells to investigate how M2-exos modulate ferroptosis. We found that M2-exos were internalized by HT-22 cells and significantly attenuated OGD/R-induced ferroptosis. Mechanistically, M2-exos enhanced mitophagy, which was mediated by the upregulation of FUN14 domain-containing protein 1 (FUNDC1), thereby inhibiting ferroptosis. Further analysis revealed that M2-exos activated FUNDC1-dependent mitophagy through the AMP-activated protein kinase (AMPK)/UNC-51-like kinase 1 (ULK1) signaling pathway. Taken together, these findings suggest that M2-exos ameliorate I/R-induced neuronal ferroptosis by enhancing FUNDC1-mediated mitophagy through the activation of AMPK/ULK1 signaling pathway.https://doi.org/10.1038/s41598-025-03091-8MicrogliaExosomeFerroptosisMitophagyIschemia/reperfusion |
| spellingShingle | Jian Li Qing Chen Hao Gu M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling Scientific Reports Microglia Exosome Ferroptosis Mitophagy Ischemia/reperfusion |
| title | M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling |
| title_full | M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling |
| title_fullStr | M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling |
| title_full_unstemmed | M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling |
| title_short | M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling |
| title_sort | m2 microglia derived exosomes reduce neuronal ferroptosis via fundc1 mediated mitophagy by activating ampk ulk1 signaling |
| topic | Microglia Exosome Ferroptosis Mitophagy Ischemia/reperfusion |
| url | https://doi.org/10.1038/s41598-025-03091-8 |
| work_keys_str_mv | AT jianli m2microgliaderivedexosomesreduceneuronalferroptosisviafundc1mediatedmitophagybyactivatingampkulk1signaling AT qingchen m2microgliaderivedexosomesreduceneuronalferroptosisviafundc1mediatedmitophagybyactivatingampkulk1signaling AT haogu m2microgliaderivedexosomesreduceneuronalferroptosisviafundc1mediatedmitophagybyactivatingampkulk1signaling |