ArticleHuman molecular genetics2014
Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 79 citations in OpenAlex.
- 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
- Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial.EClinicalMedicine · 2024Article
- Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.Journal of translational medicine · 2024Article
- Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.Brain communications · 2024Article
- Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes.Journal of biosciences · 2024Review
- 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
- Gut dysmotility in children with neurological impairment: the nutritional management.Frontiers in neurology · 2023Review
- Boosting Mitochondrial Potential: An Imperative Therapeutic Intervention in Amyotrophic Lateral Sclerosis.Current neuropharmacology · 2023Review
- Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells.International journal of molecular sciences · 2022Article
- Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit.Communications biology · 2022Article
- CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative.Clinical genetics · 2022Review
- Entecavir competitively inhibits deoxyguanosine and deoxyadenosine phosphorylation in isolated mitochondria and the perfused rat heart.The Journal of biological chemistry · 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
- Therapy Prospects for Mitochondrial DNA Maintenance Disorders.International journal of molecular sciences · 2021Review
- Regulatory environment for novel therapeutic development in mitochondrial diseases.Journal of inherited metabolic disease · 2021Review
- 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
- Pioglitazone and Deoxyribonucleoside Combination Treatment Increases Mitochondrial Respiratory Capacity in m.3243A>G MELAS Cybrid Cells.International journal of molecular sciences · 2020Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several deoxyribonucleoside triphosphates (dNTPs), and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of deoxyguanosine kinase-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides (dNs) involved in each biochemical defect (deoxyguanosine or deoxycytidine, dCtd) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of dN catabolism using tetrahydrouridine (THU; inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using an MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of dCtd or THU. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. We propose increasing cellular availability of the deficient dNTP precursor by direct administration of the dN or inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism.
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