ArticleEBioMedicine2019
Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 36 citations in OpenAlex.
- Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1EMBO molecular medicine · 2026Article
- Mitochondrial disease management through phytochemical interventions.Molecular and cellular biochemistry · 2025Review
- Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.Human molecular genetics · 2025Article
- Mitochondrial diseases: from molecular mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.Annals of neurology · 2024Article
- Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using YeastInternational journal of molecular sciences · 2023Review
- Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells.International journal of molecular sciences · 2022Article
- A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool.International journal of molecular sciences · 2021Article
- Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency.Annals of neurology · 2021Article
- Therapy Prospects for Mitochondrial DNA Maintenance Disorders.International journal of molecular sciences · 2021Review
- Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.International journal of molecular sciences · 2021Article
- Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease.Frontiers in cardiovascular medicine · 2021Review
- Current progress in the therapeutic options for mitochondrial disorders.Physiological research · 2020Article
- Deoxynucleoside therapy for respiratory involvement in adult patients with thymidine kinase 2-deficient myopathy.BMJ open respiratory research · 2020Observational
- Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency.BMC molecular and cell biology · 2020Article
- Insights into deoxyribonucleoside therapy for mitochondrial TK2 deficient mtDNA depletion.EBioMedicine · 2019Article
- Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency.EBioMedicine · 2019Article
- Mitochondrial DNA maintenance defects: potential therapeutic strategies.Molecular genetics and metabolismReview
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThymidine kinase 2 (TK2) catalyses the phosphorylation of deoxythymidine (dThd) and deoxycytidine (dCtd) within mitochondria. TK2 deficiency leads to mtDNA depletion or accumulation of multiple deletions. In patients, TK2 mutations typically manifest as a rapidly progressive myopathy with infantile onset, leading to respiratory insufficiency and encephalopathy in the most severe clinical presentations. TK2-deficient mice develop the most severe form of the disease and die at average postnatal day 16. dThd+dCtd administration delayed disease progression and expanded lifespan of a knockin murine model of the disease.
methodsWe daily administered TK2 knockout mice (Tk2
findingsdThd+dCtd treatment extended average lifespan of Tk2
interpretationdThd+dCtd treatment recruits alternative cytosolic salvage pathways for dNTP synthesis, suggesting that this therapy would be of benefit for any Tk2 mutation. dThd accounts for the therapeutic effect of the combined treatment in mice. During the first weeks after birth, mice experience marked tissue-specific metabolic regulations and ontogenetic changes in dNTP metabolism-related enzymes that limit therapeutic efficacy to early developmental stages. FUND: This study was funded by grants from the Spanish Ministry of Industry, Economy and Competitiveness, the Spanish Instituto de Salud Carlos III, the Fundación Inocente, Inocente, AFM Téléthon and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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