ArticleHuman molecular genetics2009
Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling.
Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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87 citing papers in PubMed, 136 citations in OpenAlex.
- Comprehensive Insights into Perrault Syndrome: Genetic Diversity and Clinical Implications.Reproductive sciences (Thousand Oaks, Calif.) · 2026Review
- Human mitochondrial helicase Twinkle has RNA binding, annealing, and strand-exchange activities.Nucleic acids research · 2026Article
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA replication defects.Human genetics · 2025Article
- Single-molecule fluorescence reveals the DNA unwinding mechanism of mitochondrial helicase TWINKLE and its interplay with single-stranded DNA-binding proteins.Nucleic acids research · 2025Article
- Retromer promotes the lysosomal turnover of mtDNA.Science advances · 2025Article
- Identification of genetic mechanisms of non-isolated auditory neuropathy with various phenotypes in Chinese families.Orphanet journal of rare diseases · 2025Article
- Mitochondrial DNA depletion syndrome and its cardiac complication.Frontiers in cardiovascular medicine · 2025Review
- Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.Nature communications · 2024Article
- Mitochondrial Chronic Progressive External Ophthalmoplegia.Brain sciences · 2024Review
- Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?International journal of molecular sciences · 2023Review
- Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells.Nucleic acids research · 2023Article
- Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity.Molecules (Basel, Switzerland) · 2023Review
- Analysis of Mitochondrial DNA Replication by Two-Dimensional Agarose Gel Electrophoresis.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.Nature communications · 2022Article
- Method for the structural analysis of Twinkle mitochondrial DNA helicase by cryo-EM.Methods (San Diego, Calif.) · 2022Article
- Top3α is the replicative topoisomerase in mitochondrial DNA replication.Nucleic acids research · 2022Article
- Structural insight and characterization of human Twinkle helicase in mitochondrial disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Decrease of MtDNA copy number affects mitochondrial function and involves in the pathological consequences of ischaemic stroke.Journal of cellular and molecular medicine · 2022Article
- Mammalian Resilience Revealed by a Comparison of Human Diseases and Mouse Models Associated With DNA Helicase Deficiencies.Frontiers in molecular biosciences · 2022Review
27 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 4 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Mutations in the mitochondrial helicase Twinkle underlie autosomal dominant progressive external ophthalmoplegia (PEO), as well as recessively inherited infantile-onset spinocerebellar ataxia and rare forms of mitochondrial DNA (mtDNA) depletion syndrome. Familial PEO is typically associated with the occurrence of multiple mtDNA deletions, but the mechanism by which Twinkle dysfunction induces deletion formation has been under debate. Here we looked at the effects of Twinkle adPEO mutations in human cell culture and studied the mtDNA replication in the Deletor mouse model, which expresses a dominant PEO mutation in Twinkle and accumulates multiple mtDNA deletions during life. We show that expression of dominant Twinkle mutations results in the accumulation of mtDNA replication intermediates in cell culture. This indicated severe replication pausing or stalling and caused mtDNA depletion. A strongly enhanced accumulation of replication intermediates was evident also in six-week-old Deletor mice compared with wild-type littermates, even though mtDNA deletions accumulate in a late-onset fashion in this model. In addition, our results in cell culture pointed to a problem of transcription that preceded the mtDNA depletion phenotype and might be of relevance in adPEO pathophysiology. Finally, in vitro assays showed functional defects in the various Twinkle mutants and broadly agreed with the cell culture phenotypes such as the level of mtDNA depletion and the level of accumulation of replication intermediates. On the basis of our results we suggest that mtDNA replication pausing or stalling is the common consequence of Twinkle PEO mutations that predisposes to multiple deletion formation.
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