ArticleNature metabolism2019
Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.
Article in Nature metabolism, 2019. 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 53 papers.
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Who cites it
53 citing papers in PubMed, 84 citations in OpenAlex.
- Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.Science advances · 2026Article
- Metabolites with a message: impacts on epigenetics and implications for epimetabopathies.EMBO reports · 2026Review
- Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.Science advances · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Review
- Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.iScience · 2026Article
- The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.Science advances · 2026Article
- Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis.EMBO reports · 2026Article
- Nucleotide salvage, genome instability, and potential therapeutic applications.Nucleic acids research · 2026Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- High tide or low tide: the transport and metabolism of mitochondrial nucleotides.The Biochemical journal · 2025Review
- Mitochondria protect against an intracellular pathogen by restricting access to folate.Science (New York, N.Y.) · 2025Article
- Activating AMPK improves pathological phenotypes due to mtDNA depletion.The FEBS journal · 2025Article
- Mitochondrial DNA signals driving immune responses: Why, How, Where?Cell communication and signaling : CCS · 2025Review
- Nanoengineering of Phosphate/Phosphonate Drugs via Competitive Replacement with Metal-Phenolic Networks to Overcome Breast Tumor with Lung and Bone Metastasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.Biogerontology · 2024Review
- Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.Nature communications · 2024Article
- Creatine and L-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish.Scientific reports · 2024Article
- Replication stress as a driver of cellular senescence and aging.Communications biology · 2024Review
- Biomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review.Aging and disease · 2024Review
Corrections and comments
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- Erratum issued
Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5'-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism for mouse progerias. Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited.
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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.