Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders
Abstract Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as a critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption of ho...
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| Format: | Article |
| Language: | English |
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BMC
2025-02-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03363-0 |
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| _version_ | 1823861702273269760 |
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| author | Guangming Zhang Huayuan Wei Anliu Zhao Xu Yan Xiaolu Zhang Jiali Gan Maojuan Guo Jie Wang Fayan Zhang Yifang Jiang Xinxing Liu Zhen Yang Xijuan Jiang |
| author_facet | Guangming Zhang Huayuan Wei Anliu Zhao Xu Yan Xiaolu Zhang Jiali Gan Maojuan Guo Jie Wang Fayan Zhang Yifang Jiang Xinxing Liu Zhen Yang Xijuan Jiang |
| author_sort | Guangming Zhang |
| collection | DOAJ |
| description | Abstract Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as a critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption of homeostatic regulation, and abnormalities in mitochondrial dynamics. The escaped mtDNA activates cytosolic DNA sensors, especially cyclic gmp-amp synthase (cGAS) signalling and inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating a spectrum of neurological pathologies. The therapeutic promise of targeting mtDNA leakage is discussed in detail, underscoring the necessity for a multifaceted strategy that encompasses the preservation of mtDNA homeostasis, prevention of membrane leakage, reestablishment of mitochondrial dynamics, and inhibition the activation of cytosolic DNA sensors. Advancing our understanding of the complex interplay between mtDNA leakage and neuroinflammation is imperative for developing precision therapeutic interventions for neurological disorders. |
| format | Article |
| id | doaj-art-1ee6ce3be66d46dba4f5e2f4d0446733 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-1ee6ce3be66d46dba4f5e2f4d04467332025-02-09T12:48:13ZengBMCJournal of Neuroinflammation1742-20942025-02-0122113910.1186/s12974-025-03363-0Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disordersGuangming Zhang0Huayuan Wei1Anliu Zhao2Xu Yan3Xiaolu Zhang4Jiali Gan5Maojuan Guo6Jie Wang7Fayan Zhang8Yifang Jiang9Xinxing Liu10Zhen Yang11Xijuan Jiang12School of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineHeart Disease Department, Tianjin Academy of Traditional Chinese Medicine Affiliated HospitalSchool of Traditional Chinese Medicine, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineSchool of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineSchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineAbstract Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as a critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption of homeostatic regulation, and abnormalities in mitochondrial dynamics. The escaped mtDNA activates cytosolic DNA sensors, especially cyclic gmp-amp synthase (cGAS) signalling and inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating a spectrum of neurological pathologies. The therapeutic promise of targeting mtDNA leakage is discussed in detail, underscoring the necessity for a multifaceted strategy that encompasses the preservation of mtDNA homeostasis, prevention of membrane leakage, reestablishment of mitochondrial dynamics, and inhibition the activation of cytosolic DNA sensors. Advancing our understanding of the complex interplay between mtDNA leakage and neuroinflammation is imperative for developing precision therapeutic interventions for neurological disorders.https://doi.org/10.1186/s12974-025-03363-0mtDNA leakageNeuroinflammationDNA sensorsInnate immunityNeurological disorders |
| spellingShingle | Guangming Zhang Huayuan Wei Anliu Zhao Xu Yan Xiaolu Zhang Jiali Gan Maojuan Guo Jie Wang Fayan Zhang Yifang Jiang Xinxing Liu Zhen Yang Xijuan Jiang Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders Journal of Neuroinflammation mtDNA leakage Neuroinflammation DNA sensors Innate immunity Neurological disorders |
| title | Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders |
| title_full | Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders |
| title_fullStr | Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders |
| title_full_unstemmed | Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders |
| title_short | Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders |
| title_sort | mitochondrial dna leakage underlying mechanisms and therapeutic implications in neurological disorders |
| topic | mtDNA leakage Neuroinflammation DNA sensors Innate immunity Neurological disorders |
| url | https://doi.org/10.1186/s12974-025-03363-0 |
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