Severe Impairment of Nucleotide Synthesis Through Inhibition of Mitochondrial Respiration

Gattermann, Norbert; Dadak, M.; Hofhaus, Götz; Wulfert, Michael; Berneburg, Mark; Loeffler, M. L.; Simmonds, H. Anne

doi:10.1081/ncn-200027545

Cited by 49 publications

(27 citation statements)

References 7 publications

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“…One mechanism whereby mitochondrial dysfunction could result in alterations in nucleotide pools is the mitochondrial dependence of a key enzyme in de novo pyrimidine biosynthesis, dihydroorotate dehydrogenase. 9 Direct pharmacologic inhibition of the electron transport chain results in decreased pyrimidine biosynthesis, 46 and a pharmacologic inhibitor of dihydroorotate dehydrogenase, leflunomide, has been reported to cause an anemia with megaloblastic features. 47 Furthermore, the demonstrated clinical efficacy of leflunomide as a potent lymphotoxin 48 suggests that an impairment of de novo pyrimidine biosynthesis may also underlie the impaired lymphopoiesis of both Polg A mice and patients with MDS.…”

Section: Discussionmentioning

confidence: 99%

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Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Chen

Logan

Hochberg

et al. 2009

Blood

104

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Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bonemarrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function. (Blood. 2009;114:4045-4053)

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Section: Discussionmentioning

confidence: 99%

“…Studies 9,46 currently are underway to explore the role of decreased de novo pyrimidine biosynthesis in the development of this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Chen

Logan

Hochberg

et al. 2009

Blood

104

View full text Add to dashboard Cite

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“…Hence, ATP produced by the mitochondria is an essential requirement to drive the cell cycle. Inhibition of mitochondrial protein synthesis leads to G 1 arrest and attenuates DNA replication (13,47), whereas increasing mitochondrial DNA copy number increases the transition from G 1 to S and G 2 to M, thereby accelerating the progression through the cell cycle (3). Our analysis of markers for cell cycle phase demonstrated that significantly more cells in the crypts of PolgD257A mice are in G 2 phase, while fewer cells are in S phase compared with WT mice.…”

Section: G921mentioning

confidence: 99%

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Fox

Magness

Kujoth

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Changes in intestinal absorption of nutrients are important aspects of the aging process. To address this issue, we investigated the impact of accelerated mitochondrial DNA mutations on the stem/progenitor cells in the crypts of Lieberkühn in mice homozygous for a mitochondrial DNA polymerase gamma mutation, Polg D257A, that exhibit accelerated aging phenotype. As early as 3–7 mo of age, the small intestine was significantly enlarged in the PolgD257A mice. The crypts of the PolgD257A mice contained 20% more cells than those of their wild-type littermates and exhibited a 10-fold increase in cellular apoptosis primarily in the stem/progenitor cell zones. Actively dividing cells were proportionally increased, yet a significantly smaller proportion of cells was in the S phase of the cell cycle. Stem cell-derived organoids from PolgD257A mice failed to develop fully in culture and exhibited fewer crypt units, indicating an impact of the mutation on the intestinal epithelial stem/progenitor cell maintenance. In addition, epithelial cell migration along the crypt-villus axis was slowed and less organized, and the ATP content in the villi was significantly reduced. On a high-fat, high-carbohydrate diet, PolgD257A mice showed significantly restricted absorption of excess lipids accompanied by an increase in fecal steatocrits. We conclude that the PolgD257A mutation causes cell cycle dysregulation in the crypts leading to the age-associated changes in the morphology of the small intestine and contributes to the restricted absorption of dietary lipids.

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“…14 Severe mtDNA depletion and secondary respiratory chain dysfunction is thought to diminish the availability of intracellular pyrimidines, because a normal electron flux through the respiratory chain is required for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme that is essential for pyrimidine de novo synthesis. 18 Intramitochondrial pyrimidine deficiency could then induce or contribute to an even more profound mtDNA-depletion by allowing the triphosphory-lated pyrimidine antiretrovirals to compete more efficiently with their natural pyrimidine counterparts at polymerase-␥. Exogenous uridine supplementation may disrupt this vicious circle by replenishing intracellular pyrimidine pools distal from DHODH through the salvage pathway.…”

mentioning

confidence: 99%

Pyrimidine Nucleoside Depletion Sensitizes to the Mitochondrial Hepatotoxicity of the Reverse Transcriptase Inhibitor Stavudine

Setzer

Lebrecht

Walker

2008

The American Journal of Pathology

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Stavudine is a hepatotoxic antiretroviral nucleoside analogue that also inhibits the replication of mitochondrial DNA (mtDNA). To elucidate the mechanism and consequences of mtDNA depletion, we treated HepG2 cells with stavudine and either redoxal, an inhibitor of de novo pyrimidine synthesis, or uridine, from which pyrimidine pools are salvaged. Compared with treatment with stavudine alone, co-treatment with redoxal accelerated mtDNA depletion, impaired cell division, and activated caspase 3. These adverse effects were completely abrogated by uridine. Intracellular ATP levels were unaffected. Transcriptosome profiling demonstrated that redoxal and stavudine acted synergistically to induce CDKN2A and p21, indicating cell cycle arrest in G 1 , as well as genes involved in intrinsic and extrinsic apoptosis. Moreover, redoxal and stavudine showed synergistic interaction in the up-regulation of transcripts encoded by mtDNA and the induction of nuclear transcripts participating in energy metabolism, mitochondrial biogenesis, oxidative stress, and DNA repair. Genes involved in nucleotide metabolism were also synergistically up-regulated by both agents; this effect was completely antagonized by uridine. Thus, pyrimidine depletion sensitizes cells to stavudine-mediated mtDNA depletion and enhances secondary cell toxicity. Our results indicate that drugs that diminish pyrimidine pools should be avoided in stavudine-treated human immunodeficiency virus patients. Uridine supplementation reverses this toxicity and, because of its good tolerability, has potential clinical value for the treatment of side effects associated with pyrimidine depletion. (Am J Pathol 2008, 172:681-690;

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Severe Impairment of Nucleotide Synthesis Through Inhibition of Mitochondrial Respiration

Cited by 49 publications

References 7 publications

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

Pyrimidine Nucleoside Depletion Sensitizes to the Mitochondrial Hepatotoxicity of the Reverse Transcriptase Inhibitor Stavudine

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