ArticleNature communications2022
Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 88 citations in OpenAlex.
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- Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment.Neoplasia (New York, N.Y.) · 2026Review
- MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.Nature structural & molecular biology · 2026Article
- Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.Pharmacological reports : PR · 2026Article
- Mitochondrial interplay with membrane organelles in health and disease.Cell communication and signaling : CCS · 2026Review
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- Early Reduction in Mitochondrial Membrane Potential in Synaptic Mitochondria Contribute to Synaptic Pathology in the EAE Mouse Model of Multiple Sclerosis.International journal of molecular sciences · 2026Article
- Cell-Free DNA-Based Theranostics for Inflammatory Disorders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mitochondria and Aging: Redox Balance Modulation as a New Approach to the Development of Innovative Geroprotectors (Fundamental and Applied Aspects).International journal of molecular sciences · 2026Review
- Exploring the role of mitochondrial dysfunction-related genes in osteoporosis using weighted gene co-expression network analysis and machine learning.European journal of medical research · 2025Article
- When Mitochondria Falter, the Barrier Fails: Mechanisms of Inner Blood-Retinal Barrier (iBRB) Injury and Opportunities for Mitochondria-Targeted Repair.International journal of molecular sciences · 2025Review
- Sensing within: Mitochondrial inside-out signal transduction.Cell chemical biology · 2025Review
- Alzheimer's Disease-Associated Amyloid-β Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity.Cancer research · 2025Article
- MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.Nature cell biology · 2025Article
- Nuclear VPS35 attenuates NHEJ repair by sequestering Ku protein.Molecular medicine (Cambridge, Mass.) · 2025Article
- The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.Life science alliance · 2025Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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