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Cited by 102Autophagy in Disease and TherapyMitochondrial Function and PathologyATP Synthase and ATPases Research

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

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Sen, Ayesha, Kallabis, Sebastian, Gaedke, Felix, Jüngst, Christian, Boix, Julia, Nüchel, Julian, Maliphol, Kanjanamas, Hofmann, Julia +4 more·2022·Nature Communications
DOI 10.1038/s41467-022-34205-9PMC PMC9640553

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Abstract

Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.

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Cited by

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Authors
Sen, A., Kallabis, S., Gaedke, F., Jüngst, C., Boix, J., Nüchel, J., Maliphol, K., Hofmann, J., Schauss, A. C., Krüger, M., Wiesner, R. J., & Pla-Martín, D.
Affiliations
University of Cologne (DE)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-07
Volume
13
Issue
1
Pages
6704-6704
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34205-9
PMC
PMC9640553
OpenAlex
W4308769679
Cited by
102
References
4
Citations by year
2026: 32 · 2025: 26 · 2024: 25 · 2023: 17 · 2022: 2
FWCI
12.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
Keywords
mitochondrial DNA damage, VPS35, ATG5, SAMM50, mitochondrial nucleoids, lysosomal degradation, rapamycin, muscle regeneration, mitochondrial dysfunction, endosomal maturation
MeSH terms
DNA, Mitochondrial, Mitochondria, Mitochondrial Proteins, Mitochondrial Membranes, Mitophagy

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