Fishing in the (deoxyribonucleotide) pool

Deoxyribonucleoside triphosphates (dNTPs) are the building blocks of DNA, and a constant supply is essential for the synthesis and maintenance of both the nuclear and mitochondrial genomes. Antiviral nucleoside analogues and inborn errors of nucleotide metabolism frequently cause dNTP pool imbalances, leading to depletion of mtDNA (mitochondrial DNA) in non-replicating tissues. mtDNA depletion, in turn, causes failure of the mitochondrial respiratory chain, resulting in cellular energy depletion and cell death. Accordingly, it is important to understand the origin and regulation of dNTPs in order to develop safe and effective treatments. In this issue of the Biochemical Journal, Morris et al. have pursued the origin of pyrimidines in perfused adult rat heart. They found no evident role for the nucleotide de novo synthesis pathway and also demonstrated that AZT (3′-azido-3′-deoxythymidine; also known as zidovudine) substantially decreased the TTP pool. Their results underscore the general importance of the mitochondrial deoxyribonucleoside salvage pathway in adult tissues, and particularly in AZT-mediated toxicity. Although the role of nucleoside salvaging versus de novo synthesis in humans remains unclear, the study of tissue cultures and animal models contribute to the understanding of the intricate network of biochemical pathways, maintaining the cellular dNTP supply.