Mitochondrial DNA polymerase

However, not all effects of NRTls on mitochondria can be explained by the DNA polymerase y hypothesis. Other mechanisms, either secondary to or independent of inhibition of DNA polymerase y are involved in NRTI toxicity (Moyle 2000a, 2000b Lewis et al. 2003). AZT is a potent inhibitor of mitochondrial DNA polymerase y but does not cause neuropathy in HIV patients (Dalakas 2001). Keswani and colleagues showed that NRTls caused direct mitochondrial toxicity through... 

There are specific fiuorescent dyes for specific pathologies created by specific drug classes, such as phospholipidosis from cationic amphiphilic drugs [18, 19], mitochondrial DNA depletion by nucleoside reverse transcriptase inhibitors that also inhibit mitochondrial DNA polymerase gamma and redox cyclers that produce reactive oxygen species. The complex mechanism of statin-induced toxicity is demonstrated vith early sublethal effects on apoptosis, mitochondrial function and calcium homeostasis [20]. 

The NRTIs inhibit cellular and mitochondrial DNA polymerases and various cellular kinases, resulting in toxicity. Toxicity varies with the state of the immune system early in the infection there is less toxicity, while late in the infection there is substantially more. All NRTIs... 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

In mammalian cells, at least eight DNA polymerases are present. DNA polymerase a is involved in the initiation of DNA synthesis at DNA replication origins and lagging strand synthesis (Wang, 1991). DNA polymerase 7is a mitochondrial DNA polymerase (Wang, 1991). Recently, bypass polymerases, such as DNA polymerase V, t. and Chave also been identified (Lindahl and Wood, 1999). These DNA polymerases are capable of continuing DNA synthesis even through bulky DNA lesions—such as UV-induced pyrimidine-dimers in the template strand (Lindahl and Wood, 1999). 

Aphidicolin, a tetracyclic diterpenoid, is a potent inhibitor of mammalian nuclear DNA polymerases, It does not affect mitochondrial DNA polymerase. 

In vitro, NRTIs reduce mitochondrial DNA, most likely by inhibiting mitochondrial DNA polymerase gamma. Heterogeneous toxicity profiles of different NRTIs in vivo may be related to variable tissue sensitivity, cell entry, and drug phosphorylation. Therefore, each NRTI has a specific adverse effect profile (Table 2 (11)), but any feature of mitochondrial toxicity must be considered with all NRTIs. A major problem of mitochondrial toxicity is its delayed onset, sometimes after several months of treatment. 

Johnson AA, Johnson KA. Fidelity of nucleotide incorporation by human mitochondrial DNA polymerase. J Biol Chem 2001 276 38090-6. 

Pinz, K.G., Shibutani, S., and Bogenha-gen, D.F. (1995) Acbon of mitochondrial DNA polymerase y at sites of base loss or oxidabve damage. J. Biol. Chem., 270, 9202-9206. 

Drugs in this class include delavirdine, efavirenz, and nevirapine. These drugs bind to viral reverse transcriptase and block DNA polymerase activity. Unlike the NRTIs, these drugs do not require intracellular phosphorylation and are not incorporated into viral DNA. None of these drugs has been associated with any clinically significant renal toxicities or specific fluid-electrolyte complications, and they do not appear to affect mitochondrial DNA polymerases. There is a... 

Ivy Sharer s AIDS was being treated with zidovudine (AZT), which also can act as an inhibitor of the mitochondrial DNA polymerase (polymerase y). A review of the drugs potential adverse effects showed that, rarely, it may cause varying degrees of mtDNA depeletion in different tissues, including skeletal muscle. The depletion may cause a severe mitochondrial myopathy, including "ragged-red fiber" accumulation within the skeletal muscle cells associated with ultrastructural abnormalities in their mitochondria. 

Klingbeil MM, Motyka SA, Englund PT. Multiple mitochondrial DNA polymerases in Trypanosoma brucei. Mol Cell 2002 10(l) 175-86. 

Torri AF, Englund PT. Purification of a mitochondrial DNA polymerase from Crithidia fasciculata. J Biol Chem 1992 267(7) 4786-92. 

Saxowsky TT, Choudhary G, Klin jeil MM et al. Trypanosoma brucei has two distinct mitochondrial DNA polymerase beta enzymes. J Biol Chem 2003 8 8. 

A. Neurotoxicify may be the result of inhibition of mitochondrial DNA polymerase and altered mitochondrial cell function. 

The evidence for independent initiation of mitochondrial DNA synthesis has been described. Do mitochondria utilize the same polymerizing enzymes as nuclei DNA polymerases have been isolated from rat liver mitochondria (Kalf and Ch ih, 1968 Meyer and Simpson, 1968) that manifest all of the requirements shown by the DNA polymerases isolated from bacterial and mammalian cells, but which display marked specificity for mitochondrial DNA as template. Mitochondrial DNA polymerase preparations appeared to be free of nuclear DNA polymerases, terminal addition enzymes, and deoxyribonucleases. These enzymes appear to replicate preferentially native, double-stranded, circular, mitochondrial DNA (Kalf and Qi ih, 1968). These findings strengthen the view that mitochondrial DNA synthesis is a self-contained process. 

Although it is generally assumed that EB acts by interfering with the mt DNA, some data of Meyer and Simpson (1969) indieate that the mitochondrial DNA polymerase itself may be the point of attack of the dye. This enzyme was reported to be much more sensitive to the drug than the nuclear enzyme. This does not explain an inhibition of mitochondrial RNA and protein synthesis. 

Mutations in POLG, which codes for the mitochondrial DNA polymerase y (poly), cause Alpers-Huttenlocher syndrome, which is associated with an increased risk of fatal valproate hepatotoxicity. The... 

In view of die mitochondrial autonomy and the existence of cell division independent neobiogenesis of these organelles it seems likely that in some respect mitochondrial ADP-ribosylation plays a role similar to that of nuclear ADP-ribosylation. There seems to exist certain links between ADP-ribosylation and mitochondrial replication. Our preliminary experiments showing an increase of ADP-ribosyl transferase activity during mitochondrial neobiogenesis are in favor of an involvement of ADP-ribosylation in mitochondrial replication. The topographical association of a part (25%) of protein ADP-ribosylation and mitochondrial DNA polymerase activities does also suggest such a relationship (11). 

Lipodystrophy is a feature of treatment with antiretroviral drugs, particularly protease inhibitors and nucleoside reverse transcriptase inhibitors. It has been attributed to inhibition of mitochondrial DNA polymerase y [53 ]. It is associated with other metabolic alterations, such as lactic acidosis, dyslipide-mia, and insulin resistance, and may in turn be associated with an increase in the longterm risk of cardiovascular diseases [54, 55 ]. It causes loss of fat from the face and limbs and can be accompanied by accumulation of fat in the trunk and the back of the neck. It affects up to 50% of the patients taking highly active antiretroviral drug treatment (HAART). 

Trifunovic A, Wredenberg A, Falkenberg M et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423. 

Studies carried out in our laboratory (Raulin et al.,1974) nevertheless suggest the need to look for other explanations which might explain the indispensable character of linoleic acid. The as yet unexplained increase in vivo in nuclear and mitochondrial DNA polymerase activity which was seen in adipose tissue enriched for linoleic acid (Launay et al., 1968,1969) has encouraged us to study the role of metabolic products of the EFAs in certain fundamental reactions of intermediary metabolism, other than that involving lipid components. ... 

---