Related Experiment Video

Updated: May 17, 2025

Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes
10:25

Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes

Published on: September 27, 2024

506

Retromer promotes the lysosomal turnover of mtDNA

Parisa Kakanj1,2, Mari Bonse3,4, Arya Kshirsagar5

  • 1Institute of Genetics, University of Cologne, Cologne, Germany.

Science Advances
|April 4, 2025
PubMed

Insights

Mitochondrial DNA (mtDNA) damage triggers a quality control pathway. Lysosomes and the retromer complex help clear damaged mtDNA, restoring mitochondrial function.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Genetics

Background:

  • Mitochondrial DNA (mtDNA) is vulnerable to cellular damage.
  • Replication stress can lead to mtDNA transfer to endosomes for degradation.

Purpose of the Study:

  • To investigate the cellular mechanisms responding to mtDNA replication stress.
  • To identify proteins involved in mitochondrial quality control and mtDNA turnover.

Main Methods:

  • Proximity biotinylation to map protein interactions during mtDNA stress.
  • Utilized a Drosophila model with a long deletion on mtDNA (ΔmtDNA).
  • Investigated the role of the retromer complex, specifically VPS35.

Main Results:

  • mtDNA stress rewires the mitochondrial proteome, increasing association with lysosomal and vesicle proteins.
  • The retromer complex, via VPS35, extracts mitochondrial components and promotes mitochondrial-derived vesicles to lysosomes.
  • mtDNA is directly shuttled to a recycling organelle in a BAX-dependent manner.
  • ΔmtDNA activates a specific transcriptome to counteract damage, and Vps35 expression restores mtDNA homoplasmy.

Conclusions:

  • A novel quality control mechanism exists for the mitochondrial matrix.
  • Lysosomes play a crucial role in mtDNA turnover and mitigating mtDNA damage.
  • The retromer complex is essential for mitochondrial quality control and mtDNA recycling.

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