ArticlePLoS genetics2013
Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 240 papers, 1 of them a synthesis that pooled it.
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Who cites it
240 citing papers in PubMed, 1 synthesis or guideline pooled it, 370 citations in OpenAlex.
- Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review.EBioMedicine · 2022Pooled it
- Inheritance and selection of the mitochondrial genome.Nature reviews. Genetics · 2026Review
- Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.Science advances · 2026Article
- Recent advances in treating age-related macular degeneration and diabetic retinopathy: Current therapies and emerging novel approaches.GeroScience · 2026Review
- Article
- Humanin Mitigates Aβ-Induced Retinal Pigment Epithelium Injury via AMPK-Beclin1-Dependent Mitophagy.Aging cell · 2026Article
- Persistence of large mtDNA rearrangements linked to premature aging in Pol γ exonuclease-deficient mice.Nucleic acids research · 2026Article
- Placental mitochondrial DNA mutation-related oxidative stress underlies subsequent risk of adverse prognosis in sFGR twins.BMC pregnancy and childbirth · 2026Article
- Mitochondria at the heart of aging: structure, function, and failure.Journal of translational medicine · 2026Review
- Mitochondrial dysfunction in peripheral mononuclear blood cells (PBMC) of individuals with mild cognitive impairment.GeroScience · 2026Observational
- Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.Nature communications · 2026Article
- Mammalian mitochondrial DNA accumulates insertions and deletions with age in energetically demanding tissues.Molecular biology and evolution · 2026Article
- Lifespan Predicts Mitochondrial Substitution Rates across Vertebrates, but Methodology Matters.Genome biology and evolution · 2026Article
- Development of an APC and TP53-based duplex sequencing assay to positively predict colorectal cancer response to anti-EGFR therapy.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Detection of mutations: from Ames test to duplex sequencing.Frontiers in molecular biosciences · 2026Review
- Cellular heterogeneity and therapeutic response profiling of human IDH + glioma stem cell cultures.Scientific reports · 2025Article
- Mitochondrial ATP synthase 8 single-nucleotide polymorphism affects oxidative stress and survival of mice.Pflugers Archiv : European journal of physiology · 2025Article
- Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.Nature reviews. Genetics · 2025Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Brain somatic mutations in Alzheimer's disease: linking genetic mosaicism to neurodegeneration.Molecular neurodegeneration · 2025Review
180 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Mitochondrial DNA (mtDNA) is believed to be highly vulnerable to age-associated damage and mutagenesis by reactive oxygen species (ROS). However, somatic mtDNA mutations have historically been difficult to study because of technical limitations in accurately quantifying rare mtDNA mutations. We have applied the highly sensitive Duplex Sequencing methodology, which can detect a single mutation among >10(7) wild type molecules, to sequence mtDNA purified from human brain tissue from both young and old individuals with unprecedented accuracy. We find that the frequency of point mutations increases ~5-fold over the course of 80 years of life. Overall, the mutation spectra of both groups are comprised predominantly of transition mutations, consistent with misincorporation by DNA polymerase γ or deamination of cytidine and adenosine as the primary mutagenic events in mtDNA. Surprisingly, G → T mutations, considered the hallmark of oxidative damage to DNA, do not significantly increase with age. We observe a non-uniform, age-independent distribution of mutations in mtDNA, with the D-loop exhibiting a significantly higher mutation frequency than the rest of the genome. The coding regions, but not the D-loop, exhibit a pronounced asymmetric accumulation of mutations between the two strands, with G → A and T → C mutations occurring more often on the light strand than the heavy strand. The patterns and biases we observe in our data closely mirror the mutational spectrum which has been reported in studies of human populations and closely related species. Overall our results argue against oxidative damage being a major driver of aging and suggest that replication errors by DNA polymerase γ and/or spontaneous base hydrolysis are responsible for the bulk of accumulating point mutations in mtDNA.
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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.