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

The synthesis of DNA in mitochondria requires the uptake of deoxynucleotides into the matrix of the organelle. We have characterized a human cDNA encoding a member of the family of mitochondrial carriers. The protein has been overexpressed in bacteria and reconstituted into phospholipid vesicles where it catalyzed the transport of all four deoxy (d) NDPs, and, less efficiently, the corresponding dNTPs, in exchange for dNDPs, ADP, or ATP. It did not transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimidines. The physiological role of this deoxynucleotide carrier is probably to supply deoxynucleotides to the mitochondrial matrix for conversion to triphosphates and incorporation into mitochondrial DNA. The protein is expressed in all human tissues that were examined except for placenta, in accord with such a central role. The deoxynucleotide carrier also transports dideoxynucleotides efficiently. It is likely to be medically important by providing 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 therapy.

线粒体DNA的合成需要将脱氧核苷酸摄取至线粒体基质中。我们已对一种编码线粒体转运蛋白家族成员的人类互补脱氧核糖核酸（cDNA）完成功能表征。该蛋白已在细菌中实现过表达，并被重组至磷脂囊泡体系内；在此体系中，它可催化四种脱氧核苷二磷酸（dNDPs）的跨膜转运，同时以较低效率转运对应的脱氧核苷三磷酸（dNTPs），转运过程以dNDP、腺苷二磷酸（ADP）或腺苷三磷酸（ATP）作为交换底物。该蛋白无法转运脱氧核苷一磷酸（dNMPs）、核苷一磷酸（NMPs）、脱氧核苷、核苷、嘌呤或嘧啶。该脱氧核苷酸转运蛋白的生理功能大概率是向线粒体基质递送脱氧核苷酸，使其转化为三磷酸形式并整合进入线粒体DNA。除胎盘组织外，该蛋白在所有被检测的人类组织中均有表达，这与其核心生理功能相符。该脱氧核苷酸转运蛋白还可高效转运双脱氧核苷酸。该蛋白可介导核苷类似物被摄取进入线粒体，进而引发线粒体功能损伤，这正是此类药物在治疗包括艾滋病（AIDS）在内的病毒性疾病以及癌症化疗时产生毒性副作用的核心机制，因此其在医学领域具有重要研究价值。