Abstract
Mitochondrial DNA depletion caused by thymidine kinase 2 (TK2) deficiency can be compensated by a nucleoside kinase from Drosophila melanogaster (Dm-dNK) in mice. We show that transgene expression of Dm-dNK in Tk2 knock-out (Tk2(-/-)) mice extended the life span of Tk2(-/-) mice from 3 weeks to at least 20 months. The Dm-dNK(+/-)Tk2(-/-) mice maintained normal mitochondrial DNA levels throughout the observation time. A significant difference in total body weight due to the reduction of subcutaneous and visceral fat in the Dm-dNK(+/-)Tk2(-/-) mice was the only visible difference compared with control mice. This indicates an effect on fat metabolism mediated through residual Tk2 deficiency because Dm-dNK expression was low in both liver and fat tissues. Dm-dNK expression led to increased dNTP pools and an increase in the catabolism of purine and pyrimidine nucleotides but these alterations did not apparently affect the mice during the 20 months of observation. In conclusion, Dm-dNK expression in the cell nucleus expanded the total dNTP pools to levels required for efficient mitochondrial DNA synthesis, thereby compensated the Tk2 deficiency, during a normal life span of the mice. The Dm-dNK(+/-) mouse serves as a model for nucleoside gene or enzyme substitutions, nucleotide imbalances, and dNTP alterations in different tissues.
Highlights
Expression of Drosophila melanogaster nucleoside kinase (Dm-dNK) in mice causes deoxyribonucleotide pool imbalances
Mitochondrial DNA depletion caused by thymidine kinase 2 (TK2) deficiency can be compensated by a nucleoside kinase from Drosophila melanogaster (Dm-dNK) in mice
We show that transgene expression of Dm-dNK in thymidine kinase 2 (Tk2) knock-out (Tk2؊/؊) mice extended the life span of Tk2؊/؊ mice from 3 weeks to at least 20 months
Summary
Expression of Drosophila melanogaster nucleoside kinase (Dm-dNK) in mice causes deoxyribonucleotide (dNTP) pool imbalances. Mitochondrial DNA depletion caused by thymidine kinase 2 (TK2) deficiency can be compensated by a nucleoside kinase from Drosophila melanogaster (Dm-dNK) in mice. A significant difference in total body weight due to the reduction of subcutaneous and visceral fat in the Dm-dNK؉/؊Tk2؊/؊ mice was the only visible difference compared with control mice This indicates an effect on fat metabolism mediated through residual Tk2 deficiency because DmdNK expression was low in both liver and fat tissues. Dm-dNK expression in the cell nucleus expanded the total dNTP pools to levels required for efficient mitochondrial DNA synthesis, thereby compensated the Tk2 deficiency, during a normal life span of the mice. The results show that Dm-dNKϩ/ϪTk2Ϫ/Ϫ and Dm-dNKϩ/Ϫ mice survive as long as wt mice and maintain normal mtDNA levels until they are 20 months. The only phenotypic differences observed were that the Dm-dNKϩ/ϪTk2Ϫ/Ϫ mice were smaller than the wt and Dm-dNKϩ/Ϫ mice and had reduced subcutaneous and visceral fat
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