NeuralCipher Research overview
The text below is the source article’s original abstract under a verified reuse license. cc by
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.
Scientific assessment
Research question
Assess the question within the original study’s scope.
Methods & sample
Check the source article for study design and sample details.
Key findings
An editorially approved findings summary is not yet published for this record.
Limitations
Generalizability, bias and clinical meaning require separate assessment.
Methods, samples and clinical conclusions are not inferred from bibliographic metadata.