ArticleNucleic acids research2021
DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Modelling mitochondrial diseases in neuronsJournal of neuromuscular diseases · 2025Pooled it
- Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.EMBO molecular medicine · 2026Article
- Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.Nucleic acids research · 2026Article
- Model organisms in POLG-related disorders: insights from yeast to multicellular systems.Cell death & disease · 2025Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Article
- Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.Nature communications · 2025Article
- Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.Human molecular genetics · 2025Article
- Mitochondrial DNA copy number alterations: Key players in the complexity of glioblastoma (Review).Molecular medicine reports · 2025Review
- TheGenes · 2025Article
- Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.Biogerontology · 2024Review
- Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.Cell stem cell · 2024Article
- Coordinated DNA polymerization by Polγ and the region of LonP1 regulated proteolysis.Nucleic acids research · 2024Article
- mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.Nucleic acids research · 2023Article
- Let's make it clear: systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling.Nucleic acids research · 2023Article
- Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA.Nucleic acids research · 2023Article
- Mitochondrial DNA maintenance in Drosophila melanogaster.Bioscience reports · 2022Review
- Downregulating Mitochondrial DNA Polymerase γ in the Muscle Stimulated Autophagy, Apoptosis, and Muscle Aging-Related Phenotypes inBiomolecules · 2022Article
- Polymerase ζ Is Involved in Mitochondrial DNA Maintenance Processes in Concert with APE1 Activity.Genes · 2022Article
- Mitochondrial Neurodegeneration.Cells · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
20 authors at 8 institutions in 8 countries.
Funding
Abstract
Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLγB, the accessory subunit of the POLγ holoenzyme. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLγB acts to stabilize POLγA and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POLγ subunits. We suggest that targeting POLγA turnover can be exploited as a target for the development of future therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.