Astrocyte–neuron crosstalk through extracellular vesicle-shuttled miRNA-382-5p promotes traumatic brain injury
Although astrocytes undergo functional changes in response to brain injury and may be the driving force of subsequent neuronal death, the underlying mechanisms remain incompletely elucidated. Here, we showed that extracellular vesicle (EV)-shuttled miRNA-382-5p may serve as a biomarker for the severity of traumatic brain injury (TBI), as the circulating EV-miRNA-382-5p level was significantly increased in both human patients and TBI model mice. Mechanistically, astrocyte-derived EVs delivered the shuttled miRNA-382-5p to mediate astrocyte-neuron communication, which promoted neuronal mitochondrial dysfunction by inhibiting the expression of optic atrophy-1 (OPA1). Consistent with these findings, genetic ablation of neuronal OPA1 exacerbated mitochondrial damage and neuronal apoptosis in response to TBI. Moreover, engineered RVG-miRNA-382-5p inhibitor-EVs, which can selectively deliver a miRNA-382-5p inhibitor to neurons, significantly attenuated mitochondrial damage and improved neurological function after TBI. Taken together, our data suggest that EV-shuttled miRNA-382-5p may be a critical mediator of astrocyte-induced neurotoxicity under pathological conditions and that targeting miRNA-382-5p-OPA1 signaling has potential for clinical translation in the treatment of traumatic brain injury.
Authors
- B. Wang (ORCID: https://orcid.org/0009-0008-2583-0218)
- Liying Han (ORCID: https://orcid.org/0000-0001-9133-7415)
- Leiyang Li
- Chengxuan Guo (ORCID: https://orcid.org/0009-0001-4353-8850)
- Shunnan Ge (ORCID: https://orcid.org/0000-0003-1338-830X)
- Jing Feng (ORCID: https://orcid.org/0000-0001-6726-7912)
- Wenxing Cui
- Jinpeng Zhou (ORCID: https://orcid.org/0000-0002-7262-1119)
- Hao Bai (ORCID: https://orcid.org/0000-0002-5738-4186)
- Yan Qu (ORCID: https://orcid.org/0000-0001-5434-7390)
- Tinghao Wang
- Haixiao Liu (ORCID: https://orcid.org/0000-0003-0994-2005)
- Jin Wang (ORCID: https://orcid.org/0000-0001-5420-5704)
- Hao Guo (ORCID: https://orcid.org/0000-0002-3557-8289)
- Wei Guo (ORCID: https://orcid.org/0000-0002-5255-2865)
- Liang Cao (ORCID: https://orcid.org/0000-0002-7570-3136)
- Guodong Gao (ORCID: https://orcid.org/0000-0002-4203-3316)
- Xun Wu (ORCID: https://orcid.org/0000-0002-8213-3178)
- Qing Hu
- Zhenyong Wu (ORCID: https://orcid.org/0009-0009-1107-7437)
- Ting Ting Wang (ORCID: https://orcid.org/0000-0001-9962-6182)
Institutions
- Shanxi Medical University (CN)
- Chinese Academy of Sciences (CN)
- Shaanxi Provincial People's Hospital (CN)
- People's Liberation Army 401 Hospital (CN)
- Shanghai Institute of Materia Medica (CN)
- Zhejiang Provincial People's Hospital (CN)
- Tang Du Hospital (CN)
- Shanxi Provincial People’s Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Air Force Medical University (CN)
Publication Details
- Journal
- Experimental & Molecular Medicine
- Published
- 2024-12-02
- DOI
- https://doi.org/10.1038/s12276-024-01355-3
- Citations
- 18
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 4.21