MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on November 11, 2004; DOI: 10.1124/mol.104.007120

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.104.007120v1
67/2/408    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by lam, w.
Right arrow Articles by Cheng, Y.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by lam, w.
Right arrow Articles by Cheng, Y.-C.


Received for publication September 10, 2004.
Revised November 9, 2004.
Accepted for publication November 11, 2004.

Expression of Deoxynucleotide Carrier is not associated with the mitochondrial DNA depletion caused by anti-HIV dideoxynucleoside analogs and mitochondrial dNTP uptake

wing lam 1, ChingShin Chen 1, Shoulun Ruan 2, Chung Hang Leung 1, Yung-Chi Cheng 1*

1 Yale University 2 Yale Univeristy

* Address correspondence to: E-mail: cheng.lab{at}yale.edu

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-HIV dideoxynucleoside analogs in mitochondria. Recently, a protein, termed mitochondrial deoxynucleotide carrier (DNC), based on its ability to transport dNTPs in reconstituted proteoliposomes was 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 Km values for dNTPs uptake by reconstituted DNC were in the mM range which is a thousand fold higher than that of the physiological level. Further, we found that over-expressing DNC (wt and G177A-mutated DNC) in RKO cells did not sensitize the cells to the mtDNA depletion caused by ddC, d4T and ddI or affect the mtDNA recovery rate after ddC treatment. Mitochondria isolated from DNC over-expressing 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 siRNA 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 TK2 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.


Key words: Nucleoside/Nucleotide, DNA damage and repair, Nucleoside/Nucleotide derivatives


This article has been cited by other articles:


Home page
 FASEB J.Home page
C. K. Mathews and S. Song
Maintaining precursor pools for mitochondrial DNA replication
FASEB J, August 1, 2007; 21(10): 2294 - 2303.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
J. Satrustegui, B. Pardo, and A. del Arco
Mitochondrial Transporters as Novel Targets for Intracellular Calcium Signaling
Physiol Rev, January 1, 2007; 87(1): 29 - 67.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. J. Lindhurst, G. Fiermonte, S. Song, E. Struys, F. De Leonardis, P. L. Schwartzberg, A. Chen, A. Castegna, N. Verhoeven, C. K. Mathews, et al.
Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia
PNAS, October 24, 2006; 103(43): 15927 - 15932.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics