Deoxyribonucleotide Pool Imbalance Stimulates Deletions in HeLa Cell Mitochondrial DNA

Song, Shiwei; Wheeler, Linda J.; Mathews, Christopher K.

doi:10.1074/jbc.c300401200

Cited by 112 publications

(109 citation statements)

References 37 publications

(43 reference statements)

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“…The depletion of mtDNA correlates with histopathological abnormalities and is likely due to toxic levels of dThd and dUrd disrupting mitochondrial nucleotide pool, as confirmed by in vitro studies. 12,23 The mechanism for this effect remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Giordano

Sebastiani

Giorgio

et al. 2008

The American Journal of Pathology

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Chronic intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic intestinal pseudo-obstruction can be a feature of mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of thymidine and deoxyuridine, and accumulate somatic mitochondrial DNA (mtDNA) defects. The present study aimed to clarify the molecular basis of chronic intestinal pseudoobstruction in MNGIE. Using laser capture microdissection, we correlated the histopathological features with mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in the small vessel wall. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Giordano

Sebastiani

Giorgio

et al. 2008

The American Journal of Pathology

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“…Mitochondrial nucleotide pools were prepared as per Song et al (6). Briefly, MEFs were harvested in 20 150-mm dishes by trypsinization.…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial isolation and preparation of extracts were as described in ref. 6. rNTP pools were determined by HPLC using a Hewlett-Packard 1050 system with 260-nm detection.…”

Section: Methodsmentioning

confidence: 99%

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Lindhurst

Fiermonte

Song

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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140

135

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SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to ␣-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated ␣-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo-and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein.The mitochondria of Slc25a19 ؊/؊ and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the ␣-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development.development ͉ mitochondrial transporter ͉ mouse model ͉ thiamine pyrophosphate deficiency ͉ neural tube defect

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“…It is conceivable that mitochondrial damage contributes to muta-genesis of the nuclear genome in part due to impaired nucleotide biosynthesis. In fact, it is well established that an imbalance in the dNTP pool is mutagenic to cells [25]. Studies demonstrate that a dNTP pool imbalance can induce nucleotide insertion, frame-shift mutation [25] sister chromatid exchange, recombination and doublestrand break [26].…”

Section: Mitochondrial Damagementioning

confidence: 99%

Protection Against Oxidative Stress and “IGF-I Deficiency Conditions”

Morón¹,

Castilla‐Cortázar²

2012

Antioxidant Enzyme

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Deoxyribonucleotide Pool Imbalance Stimulates Deletions in HeLa Cell Mitochondrial DNA

Abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder as-

Cited by 112 publications

References 37 publications

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Protection Against Oxidative Stress and “IGF-I Deficiency Conditions”

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