MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.

ABSTRACT: Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required fo

SUBMITTER: Nguyen M 

PROVIDER: S-EPMC12527936 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature