Deoxyribonucleoside Kinases in Mitochondrial DNA Depletion
| Autor: | Ann Saada-Reisch |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Mitochondrial DNA
Mitochondrial disease Respiratory chain Down-Regulation Mitochondrion Deoxyguanosine kinase DNA Mitochondrial Thymidine Kinase Biochemistry chemistry.chemical_compound Cytosol Muscular Diseases Genetics medicine Humans Muscle Skeletal Nucleotide salvage chemistry.chemical_classification Chemistry DNA General Medicine Deoxycytidine kinase medicine.disease Molecular biology Mitochondria Cell biology Deoxyribonucleoside Phosphotransferases (Alcohol Group Acceptor) Enzyme Mutation Molecular Medicine |
| Zdroj: | Nucleosides, Nucleotides and Nucleic Acids. 23:1205-1215 |
| ISSN: | 1532-2335 1525-7770 |
| Popis: | Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a heterogeneous group of mitochondrial disorders, manifested by a decreased mtDNA copy number and respiratory chain dysfunction. Primary MDS are inherited autosomally and may affect a single organ or multiple tissues. Mutated mitochondrial deoxyribonucleoside kinases; deoxyguanosine kinase (dGK) and thymidine kinase 2 (TK2), were associated with the hepatocerebral and myopathic forms of MDS respectively. dGK and TK2 are key enzymes in the mitochondrial nucleotide salvage pathway, providing the mitochondria with deoxyribonucleotides (dNP) essential for mtDNA synthesis. Although the mitochondrial dNP pool is physically separated from the cytosolic one, dNP's may still be imported through specific transport. Non-replicating tissues, where cytosolic dNP supply is down regulated, are thus particularly vulnerable to dGK and TK2 deficiency. The overlapping substrate specificity of deoxycytidine kinase (dCK) may explain the relative sparing of muscle in dGK deficiency, while low basal TK2 activity render this tissue susceptible to TK2 deficiency. The precise pathophysiological mechanisms of mtDNA depletion due to dGK and TK2 deficiencies remain to be determined, though recent findings confirm that it is attributed to imbalanced dNTP pools. |
| Databáze: | OpenAIRE |
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