Mitochondrial 8-Oxoguanine DNA Glycosylase 1-Mitochondrial Permeability Transition Pore Axis Drives Mitochondrial DNA Escape and Accelerates Osteoarthritis Progression

Mitochondrial DNA (mtDNA) damage and its subsequent release into the cytoplasm are strongly linked to osteoarthritis (OA), but the pathogenic mechanism remains poorly understood. Here, this study reveals that under inflammatory or oxidative stress, the down-regulation of mitochondrial base excision repair enzyme 8-oxoguanine DNA glycosylase 1 and excessive opening of the mitochondrial permeability transition pore jointly drive mtDNA escape into the cytoplasm. Activation of 8-oxoguanine DNA glycosylase 1 with TH10785 reduces the production of oxidized mtDNA and preserves mtDNA integrity, while suppression of excessive mitochondrial permeability transition pore opening with cyclosporin A prevents mtDNA translocation. The combined intervention synergistically decreases cytosolic mtDNA levels, alleviating cartilage matrix degradation and cellular senescence. Mechanistically, cytosolic mtDNA induces the senescence-associated secretory phenotype by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-nuclear factor κB signaling axis, whereas combined intervention blocks this cascade activation. Notably, intra-articular injection of the combination of TH10785 and cyclosporin A markedly reduces senescence and ameliorates the progression of the experimental OA model mice. This research reveals the dual regulatory roles of mtDNA integrity and translocation in governing cytosolic mtDNA content, providing novel insights for developing mtDNA-targeted therapeutic strategies against OA.