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

作者：Guangming Zhang, Huayuan Wei, Anliu Zhao, Yan Xu, Xiaolu Zhang, Jiali Gan, Maojuan Guo, Jie Wang, Fayan Zhang, Yifang Jiang, Xinxing Liu, Zhen Yang, Xijuan Jiang · 发表于：Journal of Neuroinflammation · 年份：2025 · DOI：10.1186/s12974-025-03363-0 · 被引用次数：63 · 研究领域：Mitochondrial Function and Pathology、interferon and immune responses、Inflammasome and immune disorders

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.