Uridine in the Prevention and Treatment of Nrti-Related Mitochondrial Toxicity

Walker, Ulrich A.; Venhoff, Nils

doi:10.1177/135965350501002s13

Cited by 44 publications

(1 citation statement)

References 61 publications

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“…Through BCB selection, we have further tested the hypothesis that oocyte mtDNA replication, and, therefore, oocyte competence, is dependent on correct expression of TFAM and POLG. Finally, we have demonstrated the importance of mtDNA replication for successful oocyte maturation using the inhibitor, 2 0 ,3 0 -dideoxycytidine (ddC) [34].…”

Section: Introductionmentioning

confidence: 99%

Regulated Mitochondrial DNA Replication During Oocyte Maturation Is Essential for Successful Porcine Embryonic Development

Spikings

Alderson

John

2007

Biology of Reproduction

233

202

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Cellular ATP is mainly generated through mitochondrial oxidative phosphorylation, which is dependent on mitochondrial DNA (mtDNA). We have previously demonstrated the importance of oocyte mtDNA for porcine and human fertilization. However, the role of nuclear-encoded mitochondrial replication factors during oocyte and embryo development is not yet understood. We have analyzed two key factors, mitochondrial transcription factor A (TFAM) and polymerase gamma (POLG), to determine their role in oocyte and early embryo development. Competent and incompetent oocytes, as determined by brilliant cresyl blue (BCB) dye, were assessed intermittently during the maturation process for TFAM and POLG mRNA using real-time RT-PCR, for TFAM and POLG protein using immunocytochemistry, and for mtDNA copy number using real-time PCR. Analysis was also carried out following treatment of maturing oocytes with the mtDNA replication inhibitor, 2',3'-dideoxycytidine (ddC). Following in vitro fertilization, preimplantation embryos were also analyzed. Despite increased levels of TFAM and POLG mRNA and protein at the four-cell stage, no increase in mtDNA copy number was observed in early preimplantation development. To compensate for this, mtDNA appeared to be replicated during oocyte maturation. However, significant differences in nuclear-encoded regulatory protein expression were observed between BCB(+) and BCB(-) oocytes and between untreated oocytes and those treated with ddC. These changes resulted in delayed mtDNA replication, which correlated to reduced fertilization and embryonic development. We therefore conclude that adherence to the regulation of the timing of mtDNA replication during oocyte maturation is essential for successful embryonic development.

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Section: Introductionmentioning

confidence: 99%

Regulated Mitochondrial DNA Replication During Oocyte Maturation Is Essential for Successful Porcine Embryonic Development

Spikings

Alderson

John

2007

Biology of Reproduction

233

202

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Uridine supplementation antagonizes zidovudine‐induced mitochondrial myopathy and hyperlactatemia in mice

Lebrecht

Deveaud

Beauvoit

et al. 2007

Arthritis & Rheumatism

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Objective. Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor.Methods. BALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks.Results. Zidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA-encoded cytochrome c oxidase I subunit, but not of nucleus-encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity.Conclusion. Our findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.Zidovudine is a nucleoside analog reverse transcriptase inhibitor (NRTI) that is widely used in the antiretroviral treatment of patients infected with the human immunodeficiency virus (HIV). A major limitation of long-term use of zidovudine is the occurrence of mitochondrial myopathy. Patients taking zidovudine may also experience an elevation in serum lactate, which may even serve as a noninvasive test for the presence of myopathy (1). A decreased intramuscular copy number of mitochondrial DNA (mtDNA) probably plays an important role in the pathogenesis of myopathy (2-4), but the exact mechanism of mtDNA depletion is under debate. Some NRTIs are thought to interfere with the mitochondrial metabolism by impairing the activity of polymerase-gamma, the enzyme which replicates mtDNA. Dideoxynucleoside analogs (stavudine, didanosine, and zalcitabine) are the drugs most commonly implicated (5), with zalcitabine being the strongest inhibitor of polymerase-gamma. Zidovudine, however, is only a weak inhibitor of polymerase-gamma (5).Results of recent studies indicate that zidovudine may cause mtDNA depletion by a different mechanism, Supported by the DFG (grant WA...

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Pharmacologic effects on mitochondrial function

Cohen

2010

Dev Disabil Res Revs

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The vast majority of energy necessary for cellular function is produced in mitochondria. Free-radical production and apoptosis are other critical mitochondrial functions. The complex structure, electrochemical properties of the inner mitochondrial membrane (IMM), and genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) are some of the unique features that explain why the mitochondria are vulnerable to environmental injury. Because of similarity to bacterial translational machinery, mtDNA translation is likewise vulnerable to inhibition by some antibiotics. The mechanism of mtDNA replication, which is required for normal mitochondrial maintenance and duplication, is inhibited by a relatively new class of drugs used to treat AIDS. The electrochemical gradient maintained by the IMM is vulnerable to many drugs that are weak organic acids at physiological pH, resulting in excessive free-radical generation and uncoupling of oxidative phosphorylation. Many of these drugs can cause clinical injury in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. The spectrum of drug-induced mitochondrial dysfunction extends across many drug classes. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of mitochondrial drug toxicity and patient safety.

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Uridine in the Prevention and Treatment of Nrti-Related Mitochondrial Toxicity

Cited by 44 publications

References 61 publications

Regulated Mitochondrial DNA Replication During Oocyte Maturation Is Essential for Successful Porcine Embryonic Development

Regulated Mitochondrial DNA Replication During Oocyte Maturation Is Essential for Successful Porcine Embryonic Development

Uridine supplementation antagonizes zidovudine‐induced mitochondrial myopathy and hyperlactatemia in mice

Pharmacologic effects on mitochondrial function

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