2. Academic Validation
  3. Retromer promotes the lysosomal turnover of mtDNA

Retromer promotes the lysosomal turnover of mtDNA

  • Sci Adv. 2025 Apr 4;11(14):eadr6415. doi: 10.1126/sciadv.adr6415.
Parisa Kakanj 1 2,  Mari Bonse 3 4,  Arya Kshirsagar 5,  Aylin Gökmen 3 4,  Felix Gaedke 2,  Ayesha Sen 5,  Belén Mollá 6,  Elisabeth Vogelsang 7,  Astrid Schauss 2,  Andreas Wodarz 2 4 7,  David Pla-Martín 3 4 5
Affiliations

Affiliations

  • 1 Institute of Genetics, University of Cologne, Cologne, Germany.
  • 2 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • 3 Institute of Physiology, University Clinics and Faculty of Medicine, University of Cologne, Cologne, Germany.
  • 4 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • 5 Institute of Biochemistry and Molecular Biology, University Clinics and Faculty of Medicine, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
  • 6 Independent Researcher, Valencia, Spain.
  • 7 Department of Molecular Cell Biology, Institute I for Anatomy. University Clinics and Faculty of Medicine, University of Cologne, Cologne, Germany.
PMID: 40184468 DOI: 10.1126/sciadv.adr6415
Abstract

Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.

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