A Review Comparing Deoxyribonucleoside Triphosphate (dNTP) Concentrations in the Mitochondrial and Cytoplasmic Compartments of Normal and Transformed Cells

Abstract

The deoxyribonucleoside triphosphate (dNTP) pools that support the replication of mitochondrial DNA are physically separated from the rest of the cell by the double membrane of the mitochondria. Perturbed homeostasis of mitochondrial dNTP pools is associated with a set of severe diseases collectively termed mitochondrial DNA depletion syndromes. The degree of interaction of the mitochondrial dNTP pools with the corresponding dNTP pools in the cytoplasm is currently not clear. We reviewed the literature on previously reported simultaneous measurements of mitochondrial and cytoplasmic deoxyribonucleoside triphosphate pools to investigate and quantify the extent of the influence of the cytoplasmic nucleotide metabolism on mitochondrial dNTP pools. We converted the reported measurements to concentrations creating a catalog of paired mitochondrial and cytoplasmic dNTP concentration measurements. Over experiments from multiple laboratories, dNTP concentrations in the mitochondria are highly correlated with dNTP concentrations in the cytoplasm in normal cells in culture (Pearson R = 0.79, p = 3 × 10-7) but not in transformed cells. For dTTP and dATP there was a strong linear relationship between the cytoplasmic and mitochondrial concentrations in normal cells. From this linear model we hypothesize that the salvage pathway within the mitochondrion is only capable of forming a concentration of approximately 2 μM of dTTP and dATP, and that higher concentrations require transport of deoxyribonucleotides from the cytoplasm.

Heart Mitochondrial TTP Synthesis and the Compartmentalization of TMP

“…Outside of S phase, and in nondividing cells, dNTPs are required only for DNA repair and for mitochondrial DNA replication, which occurs continuously in all cells. However, the amount of dNTPs required outside of S phase is decreased substantially (2).…”

“…Depending on the cell type and physiological conditions, dNTPs may be provided from ribonucleoside salvage or the de novo synthesis of ribonucleotide diphosphates followed by reduction to dNDPs by ribonucleotide reductase (RNR) 2 with subsequent phosphorylation by cellular nucleoside diphosphokinases (NDPKs) to dNTPs (for a review, see Ref. 3).…”

Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

“…Following this period, while growth continues, cell division stops and growth is due to hypertrophy (24,25). In cell culture, it is well known that the size of the dNTP pools and the expression of enzymes responsible for their synthesis and salvage are much higher in dividing cells than in quiescent cells (31). We have shown in this study that a similar change takes place in vivo, in which dNTP pools and the enzymes responsible for their synthesis and salvage decreased dramatically as heart tissue moved from hyperplasia to hypertrophy (Fig.…”

Human Cytomegalovirus Can Procure Deoxyribonucleotides for Viral DNA Replication in the Absence of Retinoblastoma Protein Phosphorylation

“…Quiescent cells maintain low levels of nucleotides that can be generated by salvage pathways to support transcription and DNA repair (28,55). Even the modest needs of retroviruses for dNTPs during reverse transcription overburden this supply (56,57).…”