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

The synthesis of DNA in mitochondria requires the uptake of deoxynucleotide s into the matrix of the organelle. We have characterized a human cDNA enco ding a member of the family of mitochondrial carriers. The protein has been overexpressed in bacteria and reconstituted into phospholipid vesicles whe re it catalyzed the transport of all four deoxy (d) NDPs, and, less efficie ntly, the corresponding dNTPs, in exchange for dNDPs, ADP, or ATP. It did n ot transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimi dines. The physiological role of this deoxynucleotide carrier is probably t o supply deoxynucleotides to the mitochondrial matrix for conversion to tri phosphates and incorporation into mitochondrial DNA. The protein is express ed in all human tissues that were examined except for placenta, in accord w ith such a central role. The deoxynucleotide carrier also transports dideox ynucleotides efficiently. It is likely to be medically important by providi ng the means of uptake into mitochondria of nucleoside analogs, leading to the mitochondrial impairment that underlies the toxic side effects of such drugs in the treatment of viral illnesses, including AIDS, and in cancer th erapy.