Abstract:
:Our previous studies suggested that the dNTP/dNDP transporter systems that exist in mitochondria for transporting dNTP/dNDP from the cytoplasm to the mitochondria for mitochondrial DNA (mtDNA) synthesis play a critical role in delayed cytotoxicity of anti-human immunodeficiency virus (HIV) dideoxynucleoside analogs in mitochondria. A protein, termed mitochondrial deoxynucleotide carrier (DNC), based on its ability to transport dNTPs in reconstituted proteoliposomes, was recently isolated. Lacking cellular information to substantiate DNC's involvement in the delayed cytotoxicity of dideoxynucleoside analogs, we expressed DNC and reconstituted it into proteoliposomes. The K(m) values for dNTPs uptake by reconstituted DNC were in the millimolar range, which is a thousandfold higher than that of the physiological level. Furthermore, we found that overexpressing DNC (wt and G177A-mutated DNC) in RKO cells did not sensitize the cells to the mtDNA depletion caused by beta-d-2',3'-dideoxycytidine (ddC), 2',3'-didehydro-2',3'-dideoxythymidine, and 2',3'-dideoxyinosine or affect the mtDNA recovery rate after ddC treatment. Mitochondria isolated from DNC-overexpressing cells did not significantly differ from that isolated from RKO cells in terms of the rate of uptake or the incorporation of dTTP into mitochondria DNA. Down-regulation of DNC expression by small interfering RNA was also ineffective in changing the action of dideoxynucleoside analogs on the mtDNA depletion and the rate of dTTP uptake into isolated mitochondria. Down-regulation of both DNC and thymidine kinase-2 also did not cause mtDNA depletion. We conclude that DNC does not play an important role in the delayed cytotoxicity (mtDNA depletion) of anti-HIV dideoxynucleoside analogs and dNTPs uptake into mitochondria.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Lam W,Chen C,Ruan S,Leung CH,Cheng YCdoi
10.1124/mol.104.007120keywords:
subject
Has Abstractpub_date
2005-02-01 00:00:00pages
408-16issue
2eissn
0026-895Xissn
1521-0111pii
mol.104.007120journal_volume
67pub_type
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