ArticleMolecular genetics and metabolism2012
In vitro supplementation with deoxynucleoside monophosphates rescues mitochondrial DNA depletion.
Article in Molecular genetics and metabolism, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04802707 (A Phase II, Monocenter, Single Arm Study To Assess The Safety and Efficacy Of Combination Deoxycytidine and Deoxythymidine For Mitochondrial Depletion Disorders), which is not on this map. Cited by 21 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase II, Monocenter, Single Arm Study To Assess The Safety and Efficacy Of Combination Deoxycytidine and Deoxythymidine For Mitochondrial Depletion Disorders
Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- A Framework for Selecting Zebrafish Models of Metabolic Diseases: Modeling Strategies, Phenotypic Validation, Mechanistic Investigation, and Efficacy Evaluation.Biomedicines · 2026Review
- Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.Science (New York, N.Y.) · 2026Article
- Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes.Frontiers in immunology · 2026Article
- Therapies for Mitochondrial Disease: Past, Present, and Future.Journal of inherited metabolic disease · 2025Review
- Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.Human molecular genetics · 2025Article
- Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.Annals of neurology · 2024Article
- Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.Frontiers in cell and developmental biology · 2024Article
- Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using YeastInternational journal of molecular sciences · 2023Review
- Crosslink between mutations in mitochondrial genes and brain disorders: implications for mitochondrial-targeted therapeutic interventions.Neural regeneration research · 2023Review
- Entecavir competitively inhibits deoxyguanosine and deoxyadenosine phosphorylation in isolated mitochondria and the perfused rat heart.The Journal of biological chemistry · 2022Article
- Review
- 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
- Therapy Prospects for Mitochondrial DNA Maintenance Disorders.International journal of molecular sciences · 2021Review
- The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency.Genetics in medicine : official journal of the American College of Medical Genetics · 2020Article
- Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok -/- zebrafish.Human molecular genetics · 2019Article
- Towards a therapy for mitochondrial disease: an update.Biochemical Society transactions · 2018Review
- DNA polymerase γ and disease: what we have learned from yeast.Frontiers in genetics · 2015Review
- Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome.Human molecular genetics · 2014Article
- Development of pharmacological strategies for mitochondrial disorders.British journal of pharmacology · 2014Review
- Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2013Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Mitochondrial DNA depletion syndromes are a genetically heterogeneous group of often severe diseases, characterized by reduced cellular mitochondrial DNA content. Investigation of potential therapeutic strategies for mitochondrial DNA depletion syndromes will be dependent on good model systems. We have previously suggested that myotubes may be the optimal model system for such studies. Here we firstly validate this technique in a diverse range of cells of patients with mitochondrial DNA depletion syndromes, showing contrasting effects in cell lines from genetically and phenotypically differing patients. Secondly, we developed a putative therapeutic approach using variable combinations of deoxynucleoside monophosphates in different types of mitochondrial DNA depletion syndromes, showing near normalization of mitochondrial DNA content in many cases. Furthermore, we used nucleoside reverse transcriptase inhibitors to precisely titrate mtDNA depletion in vitro. In this manner we can unmask a physiological defect in mitochondrial depletion syndrome cell lines which is also ameliorated by deoxynucleoside monophosphate supplementation. Finally, we have extended this model to study fibroblasts after myogenic transdifferentiation by MyoD transfection, which similar to primary myotubes also showed deoxynucleoside monophosphate responsive mitochondrial DNA depletion in vitro, thus providing a more convenient method for deriving future models of mitochondrial DNA depletion. Our results suggest that using different combinations of deoxynucleoside monophosphates depending on the primary gene defect and molecular mechanism may be a possible therapeutic approach for many patients with mitochondrial DNA depletion syndromes and is worthy of further clinical investigation.
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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 OpenQuestion graph.