GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation
Abstract Axonal fusion represents an efficient way to recover function after nerve injury. However, how axonal fusion is induced and regulated remains largely unknown. We discover that ferroptosis signaling can promote axonal fusion and functional recovery in C. elegans in a dose-sensitive manner. F...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56382-z |
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| author | Su-Hyuk Ko Kyung-Ah Cho Xin Li Qitao Ran Zhijie Liu Lizhen Chen |
| author_facet | Su-Hyuk Ko Kyung-Ah Cho Xin Li Qitao Ran Zhijie Liu Lizhen Chen |
| author_sort | Su-Hyuk Ko |
| collection | DOAJ |
| description | Abstract Axonal fusion represents an efficient way to recover function after nerve injury. However, how axonal fusion is induced and regulated remains largely unknown. We discover that ferroptosis signaling can promote axonal fusion and functional recovery in C. elegans in a dose-sensitive manner. Ferroptosis-induced lipid peroxidation enhances injury-triggered phosphatidylserine exposure (PS) to promote axonal fusion through PS receptor (PSR-1) and EFF-1 fusogen. Axon injury induces PSR-1 condensate formation and disruption of PSR-1 condensation inhibits axonal fusion. Extending these findings to mammalian nerve repair, we show that loss of Glutathione peroxidase 4 (GPX4), a crucial suppressor of ferroptosis, promotes functional recovery after sciatic nerve injury. Applying ferroptosis inducers to mouse sciatic nerves retains nerve innervation and significantly enhances functional restoration after nerve transection and resuture without affecting axon regeneration. Our study reveals an evolutionarily conserved function of lipid peroxidation in promoting axonal fusion, providing insights for developing therapeutic strategies for nerve injury. |
| format | Article |
| id | doaj-art-917da4eb35d94ee18665b768cda44e3c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-917da4eb35d94ee18665b768cda44e3c2025-02-02T12:31:27ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-025-56382-zGPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensationSu-Hyuk Ko0Kyung-Ah Cho1Xin Li2Qitao Ran3Zhijie Liu4Lizhen Chen5Barshop Institute for Longevity and Aging Studies, University of Texas Health San AntonioDepartment of Molecular Medicine, University of Texas Health San AntonioBarshop Institute for Longevity and Aging Studies, University of Texas Health San AntonioDepartment of Cell Systems and Anatomy, University of Texas Health San AntonioDepartment of Molecular Medicine, University of Texas Health San AntonioBarshop Institute for Longevity and Aging Studies, University of Texas Health San AntonioAbstract Axonal fusion represents an efficient way to recover function after nerve injury. However, how axonal fusion is induced and regulated remains largely unknown. We discover that ferroptosis signaling can promote axonal fusion and functional recovery in C. elegans in a dose-sensitive manner. Ferroptosis-induced lipid peroxidation enhances injury-triggered phosphatidylserine exposure (PS) to promote axonal fusion through PS receptor (PSR-1) and EFF-1 fusogen. Axon injury induces PSR-1 condensate formation and disruption of PSR-1 condensation inhibits axonal fusion. Extending these findings to mammalian nerve repair, we show that loss of Glutathione peroxidase 4 (GPX4), a crucial suppressor of ferroptosis, promotes functional recovery after sciatic nerve injury. Applying ferroptosis inducers to mouse sciatic nerves retains nerve innervation and significantly enhances functional restoration after nerve transection and resuture without affecting axon regeneration. Our study reveals an evolutionarily conserved function of lipid peroxidation in promoting axonal fusion, providing insights for developing therapeutic strategies for nerve injury.https://doi.org/10.1038/s41467-025-56382-z |
| spellingShingle | Su-Hyuk Ko Kyung-Ah Cho Xin Li Qitao Ran Zhijie Liu Lizhen Chen GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation Nature Communications |
| title | GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation |
| title_full | GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation |
| title_fullStr | GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation |
| title_full_unstemmed | GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation |
| title_short | GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation |
| title_sort | gpx modulation promotes regenerative axonal fusion and functional recovery after injury through psr 1 condensation |
| url | https://doi.org/10.1038/s41467-025-56382-z |
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