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Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
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MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death

Mai Nguyen1,2, Jack J Collier1,2, Olesia Ignatenko1,2

  • 1Department of Neurology and Neuroscience, Montréal Neurological Institute, McGill University, Montréal, Quebec, Canada.

Nature Cell Biology
|October 13, 2025
PubMed

Insights

Mitochondrial anchored protein ligase (MAPL) triggers inflammatory cell death (pyroptosis) by moving mitochondrial DNA to lysosomes. This pathway is implicated in neurodegenerative diseases like Parkinson's.

Area of Science:

  • Cell Biology
  • Immunology
  • Neuroscience

Background:

  • Mitochondria are crucial regulators of cell death, impacting diseases like cancer and neurodegeneration.
  • Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane ligase vital for cell survival, but its role in cell death remains undefined.

Purpose of the Study:

  • To elucidate the mechanism by which MAPL controls cell fate and survival.
  • To investigate the role of MAPL in inflammatory cell death pathways.

Main Methods:

  • Genome-wide functional genetic screening.
  • Cell biological approaches.
  • Analysis of mitochondrial DNA trafficking and lysosomal permeabilization.

Main Results:

  • MAPL overexpression induces pyroptosis via an inflammatory pathway involving mitochondria and lysosomes.
  • MAPL promotes mitochondrial DNA (mtDNA) transport in vesicles to lysosomes, leading to permeabilization and cytosolic release.
  • Released mtDNA activates the cGAS pathway, inducing cell death. Parkinson's disease-related genes (VPS35, LRRK2) also regulate this process.
  • Depletion of MAPL, LRRK2, or VPS35 inhibits inflammatory cell death in macrophages.

Conclusions:

  • MAPL is a key inducer of pyroptosis through a mitochondria-lysosome-dependent inflammatory pathway.
  • The MAPL-mediated mitochondria-lysosome pathway is central to immune signaling and cell death.
  • Dysregulation of MAPL, LRRK2, or VPS35 impacts inflammatory cell death and may contribute to neurodegenerative diseases.

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