Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of the fatty acid analogue tetradecylthioacetic acid (TTA) to rodents up-regulates peroxisomal and mitochondrial lipid-metabolizing enzymes and induces a proliferation of these organelles in hepatocytes. We show here that male NMRI mice fed a diet containing 0.3% (w/w) TTA revealed a transient two-fold increase in the incorporation of [3H]thymidine into the liver mtDNA followed by a 1.6-fold increase in the content of mtDNA. In addition, a transient three-fold increase in the mitochondrial thymidine kinase (TK2) activity and a slight increase in the DNA polymerase gamma activity was observed, indicating that the TTA induced mitochondrial proliferation is linked to an up-regulation of the mitochondrial thymidine kinase activity.
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PMID:Transient up-regulation of liver mitochondrial thymidine kinase activity in proliferating mitochondria. 1146 71

Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-gamma. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.
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PMID:Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals. 1732 72

Mitochondria within human cells contain vast numbers of mitochondrial DNA (mtDNA), which are small, circular, and double-stranded. The proper functions of mtDNA depend totally on specific proteins that are encoded by the nucleus and then imported into mitochondria. Thus instability of mtDNA can stem from the mtDNA itself, or secondarily from abnormalities in nuclear DNA. In this review, we will first introduce mtDNA, including its characteristics, replication, transcription, translation, and the proteins involved in its metabolism, in particular DNA polymerase gamma (POLG), DNA helicase Twinkle (Twinkle), and mitochondrial transcription factor A (TFAM). Secondly, we will stress the importance of mitochondrial nucleoid structures in the protection and facilitation of mtDNA metabolism, and report on the few known protein components of nucleoid, especially Twinkle, TFAM, and the recently discovered ATAD3. Based on this information, mtDNA instabilities will be categorized in accordance with their molecular etiologies, those that are caused by primary defects of mtDNA, and those by secondary effects from abnormalities in nuclear DNA. The former includes large defects or point mutations of mtDNA. The latter involves the nuclear genes of POLG1, Twinkle, ANT1, TK2, dGK, and TP. With the comprehensive categorization in this review, links are provided between the molecular and clinical aspects of mitochondrial DNA diseases. This report should help medical staff understand the complexity of these diseases and encourage them in further investigations. (
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PMID:Clinical and molecular aspects of diseases of mitochondrial DNA instability. 1966 42

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease.
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PMID:Defects in mitochondrial DNA replication and human disease. 2217 57