| First Author | Nguyen M | Year | 2025 |
| Journal | Nat Cell Biol | Volume | 27 |
| Issue | 10 | Pages | 1708-1724 |
| PubMed ID | 41083601 | Mgi Jnum | J:383201 |
| Mgi Id | MGI:8317408 | Doi | 10.1038/s41556-025-01774-y |
| Citation | Nguyen M, et al. (2025) MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death. Nat Cell Biol 27(10):1708-1724 |
| abstractText | 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 for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death. |
