Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders

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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Main Authors: 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
Format: Article
Language:English
Published: BMC 2025-02-01
Series:Journal of Neuroinflammation
Subjects:
mtDNA leakage
Neuroinflammation
DNA sensors
Innate immunity
Neurological disorders
Online Access:https://doi.org/10.1186/s12974-025-03363-0
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Summary: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.
ISSN:1742-2094

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