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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月7日

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  • 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

摘要

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.