The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Dolce, Vincenza; Fiermonte, Giuseppe; Runswick, Michael J.; Palmieri, Ferdinando; Walker, John E.

doi:10.1073/pnas.031430998

Cited by 182 publications

(163 citation statements)

References 28 publications

Supporting

Mentioning

157

Contrasting

Order By: Relevance

“…In addition, this glycine was conserved in 272 of 275 sequences in the Conserved Domain Database (www.ncbi.nlm.nih.gov͞Structure͞ cdd͞cdd.shtml). Functional data showed that SLC25A19 transported deoxynucleotides across membranes in an in vitro assay system (3). Finally, we showed that G177A SLC25A19 had no activity in this assay (2), indicating that MCPHA is associated with a SLC25A19 loss-of-function mutation.…”

mentioning

confidence: 73%

See 1 more Smart Citation

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.

Self Cite

143

138

View full text Add to dashboard Cite

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

show abstract

mentioning

confidence: 73%

“…The SLC25A19 gene also is called DNC, which stands for deoxynucleotide carrier (GenBank accession no. NM 021734) (3). SLC25A19 contains three typical mitochondrial inner mitochondrial membrane carrier motifs (4).…”

mentioning

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.

Self Cite

143

138

View full text Add to dashboard Cite

show abstract

“…One of these proteins functions as a deoxynucleotide carrier (DNC) to import phosphorylated precursors of mitochondrial (mt-) DNA synthesis and has been characterized. [1][2][3] Toxicity to mitochondria from antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) is an established side effect of AIDS therapy that limits effective treatment (reviewed in Lewis et al 4 ). Alternative combinations that are NRTI-sparing may be effective if toxicity is a significant clinical problem (reviewed in Joly et al 5 ).…”

mentioning

confidence: 99%

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Lewis

Haase

Miller

et al. 2005

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3 0 azido-3 0 -deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs. Keywords: deoxynucleotide; NRTI; AIDS; antiretroviral; mitochondrial import; DNC; cardiac; HIV The inner mitochondrial membrane contains transport proteins to move molecules into and out of the matrix. Members of the mitochondrial carrier family of proteins contain three conserved tandemrepeated sequences (B100 residues with two hydrophobic transmembrane a-helices and a hydrophilic segment thought to be an extramembranous loop 1 ). One of these proteins functions as a deoxynucleotide carrier (DNC) to import phosphorylated precursors of mitochondrial (mt-) DNA synthesis and has been characterized. 1-3 Toxicity to mitochondria from antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) is an established side effect of AIDS therapy that limits effective treatment (reviewed in Lewis et al 4 ). Alternative combinations that are NRTI-sparing may be effective if toxicity is a significant clinical problem (reviewed in Joly et al 5 ).Since DNC provides a route for mitochondrial uptake of NRTIs including zidovudine (3 0 azido-3 0 -deoxythymidine or AZT) and stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T), its role in mitochondrial NRTI import and toxicity was addressed in vivo using transgenic mice (TG) and HAART treatment. One HAART regimen included NRTIs (with either an AZT or D4T 'backbone'). A second NRTI-sparing regimen was administered in parallel as a control.DNC ov...

show abstract

“…Abnormal venous lactate levels after exercise have been reported in healthy carriers of LHON as well as in an individual with optic neuropathy. 21,22 A mitochondrial deoxynucleotide carrier, which may be the predominant means by which the NRTIs enter the mitochondria and disrupt replication, 11 has recently been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Antiretroviral drugs of the nucleoside analogue class are known to be associated with mitochondrial toxicity, for example, zidovudine can cause a toxic mitochondrial myopathy. [9][10][11] We report two similar cases to describe the severity of the clinical spectrum, and to put this association within the perspective of the relative rarity of the two conditions.…”

Section: Introductionmentioning

confidence: 93%

Leber's hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus

Mackey

Fingert

Luzhansky

et al. 2003

Eye

View full text Add to dashboard Cite

Purpose To describe the clinical features of two cases of Leber's hereditary optic neuropathy (LHON) precipitated by antiretroviral treatment for human immunodeficiency virus (HIV) infection. Methods Two cases of LHON (from an expected four new cases a year throughout Australia) were identified in men on treatment for HIV infection. Results Two HIV-infected men were receiving combination antiretroviral therapy that included nucleoside analogues. Both patients carried the 14 484 mitochondrial DNA mutation and were distantly related (seventh cousins). Although both men presented with sequential visual loss typical of LHON and one had a known close relative affected by LHON, the correct diagnosis was delayed in both cases. The final visual outcome was profoundly reduced in both instances and cessation of antiretroviral therapy did not result in recovery of vision in one patient. Conclusion Patients with a family history of LHON who require antiretroviral treatment should be warned of the high risk of severe visual loss. The underlying mechanism of antiretroviral side effects may help characterize the other trigger factors for LHON.

show abstract

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Cited by 182 publications

References 28 publications

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

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

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Leber's hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus

Contact Info

Product

Resources

About