MAPL orchestrates gasdermin-mediated release of mtDNA from lysosomes that drives pyroptotic cell death

Cell death is inhibited in cancers but increased in neurodegeneration, highlighting the importance of its regulation for human health. MAPL is an outer mitochondrial membrane SUMO ligase involved in cell death in both cancer and neurodegeneration in vivo, 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 (mtDNA) trafficking in mitochondrial-derived vesicles (MDVs) 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 for cell death. Additionally, multiple Parkinson’s disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Importantly, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-to-lysosome pathway at the nexus of immune signalling and cell death.