Micronuclear collapse under oxidative stress drives amphisome-mediated export of DNA in Parkinson disease

Abstract

The diversity of extracellular vesicle (EV) subpopulations and their impact on intercellular communication are increasingly recognized, but how organelle dysfunction shapes EV content in neurodegenerative diseases remains unclear. Mitochondrial and lysosomal functional defects are hallmarks of Parkinsons disease (PD). Here we uncover a novel pathway linking this dysfunctional axis to EV remodeling and immune activation. We show that mitochondrial reactive oxygen species (ROS) induce genomic instability and micronuclei formation in PD fibroblasts, with ruptured micronuclei being sequestered into amphisomes and exported through small EVs. These EVs are enriched in oxidized mitochondrial and nuclear DNA, which potently stimulate microglial inflammatory responses. Mechanistically, this work identifies micronuclei not as passive byproducts of genome instability but as active intermediates in EV cargo loading. Importantly, treatment with the mitochondria-targeted antioxidant AntiOxCIN4 elicited a mitohormetic response, enhancing ATM-mediated DNA damage repair, restoring mitochondrial dynamics, and improving lysosomal function. This reduced the incorporation of oxidized DNA into EVs and blunted their pro-inflammatory activity. Together, our findings reveal a previously unrecognized mechanism by which mitochondrial-lysosomal dysfunction drives the release of DNA-enriched EVs that fuel neuroinflammation in a neurodegenerative context. Targeting mitochondrial quality control to limit oxidized cargo in EVs emerges as a potential strategy to mitigate early inflammatory events in PD.