Back to Search
Start Over
Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2014 May 01; Vol. 23 (9), pp. 2459-67. Date of Electronic Publication: 2013 Dec 20. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Cells, Cultured
DNA Copy Number Variations drug effects
DNA Copy Number Variations genetics
DNA, Mitochondrial metabolism
Humans
Intestinal Pseudo-Obstruction genetics
Male
Mice, Knockout
Mitochondria drug effects
Mitochondria metabolism
Mitochondrial Encephalomyopathies genetics
Muscular Dystrophy, Oculopharyngeal
Ophthalmoplegia congenital
DNA, Mitochondrial genetics
Deoxyribonucleosides therapeutic use
Intestinal Pseudo-Obstruction drug therapy
Intestinal Pseudo-Obstruction metabolism
Mitochondrial Encephalomyopathies drug therapy
Mitochondrial Encephalomyopathies metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24362886
- Full Text :
- https://doi.org/10.1093/hmg/ddt641