ArticleGenome biology2020
Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging.
Article in Genome biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.
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Who cites it
50 citing papers in PubMed, 1 synthesis or guideline pooled it, 96 citations in OpenAlex.
- Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review.EBioMedicine · 2022Pooled it
- The Hallmarks of Aging: From Molecular Mechanisms to Clinical Translation.International journal of molecular sciences · 2026Review
- Persistence of large mtDNA rearrangements linked to premature aging in Pol γ exonuclease-deficient mice.Nucleic acids research · 2026Article
- Review
- A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mammalian mitochondrial DNA accumulates insertions and deletions with age in energetically demanding tissues.Molecular biology and evolution · 2026Article
- Cancer and Aging Biomarkers: Classification, Early Detection Technologies and Emerging Research Trends.Biosensors · 2025Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- High frequency of mitochondrial DNA rearrangements in the peripheral blood of adults with intellectual disability.Journal of intellectual disability research : JIDR · 2025Article
- Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging.Genome research · 2025Article
- Mitochondrial diseases: from molecular mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.Frontiers in pharmacology · 2025Article
- A short-lived fish with long-lasting effects: hallmarks of aging inFrontiers in aging · 2025Review
- Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.Advances in experimental medicine and biology · 2025Review
- The potential mechanism of mitochondrial homeostasis in postoperative neurocognitive disorders: an in-depth review.Annals of medicine · 2024Review
- Review
- The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies.Biomedicines · 2024Review
- Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.The Biochemical journal · 2024Review
- Article
- Uncovering Forensic Evidence: A Path to Age Estimation through DNA Methylation.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundAcquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease.
resultsTo decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns.
conclusionsThese patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
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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 Socratic graph.