From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review)

Abstract

Neurodegenerative diseases (NDDs) are commonly accompanied by persistent low-grade neuroinflammation, yet current therapies rarely achieve durable disease modification. This review aims to systematically delineate the role of mitochondrial DNA (mtDNA) leakage in linking mitochondrial injury to innate immune activation and to explore its pathological significance in NDDs. A comprehensive review of recent literature on mitochondrial stress, mtDNA release and innate immune signaling was conducted. Evidence was integrated regarding the sources of mtDNA immunogenicity, routes of mtDNA escape, mitophagy-lysosome gating mechanisms and the modulation of leakage baseline by aging and metabolic stress. Accumulating evidence indicates that cytosolic mtDNA is sensed by cyclic GMP-AMP synthase (cGAS) and activates the stimulator of interferon (IFN) genes (STING) pathway signaling through the TANK-binding kinase 1 and IFN regulatory factor 3 axis to induce type I IFN responses and promoting NF-κB-driven inflammatory transcription, thereby enhancing NLRP3 inflammasome priming. Oxidized mtDNA, pore-forming membrane events and ionic imbalance further facilitate NLRP3 assembly and pyroptotic execution, exacerbating mitochondrial damage and mtDNA release in a self-amplifying loop. Based on these findings, a modular assessment framework was proposed across the ‘input-chronicity-amplification’ layers and the potential of mtDNA-cGAS/STING-NLRP3 axis-informed stratified diagnosis and treatment was discussed Central nervous system-targeted delivery, cellular heterogeneity and immune safety windows remain critical for translational research. This review provides a testable mechanistic framework and a clinical evaluation pathway for understanding mtDNA-driven persistent inflammation in NDDs.