Parkinson’s genes orchestrate pyroptosis through selective trafficking of mtDNA to leaky lysosomes
Published October 13, 2025
Output Details
Preprint September 14, 2023
Published October 13, 2025
Description
Inflammation is an age-related factor that underlies numerous human disorders. A key driver of inflammation is the release of mitochondrial DNA (mtDNA), which binds and activates cytosolic sensors. This induces transcriptional responses and, ultimately, pyroptotic cell death. The main challenge has been to understand how mtDNA can cross the two mitochondrial membranes to access the cytosol. Through a genome-wide CRISPR knockout screen we identified a new pyroptotic pathway defined by mtDNA exit within mitochondrial- derived vesicles that are delivered to lysosomes. Critically, breach of lysosomes allows mtDNA to access cytosol, requiring multiple Parkinson's Disease-related proteins and Gasdermin pores, identified in the screen. These data place mitochondria-to-lysosome transport as a driver of pyroptosis and link multiple PD proteins along a common pathway.
Identifier (DOI)
10.1038/s41556-025-01774-y
