title: Long term expression of Drosophila melanogaster nucleoside kinase in thymidine kinase 2-deficient mice with no lethal effects caused by nucleotide pool imbalances.
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.
authors.affiliation: From the Department of Laboratory Medicine, Division of Clinical Microbiology, F68, and.
authors.forename: Shuba
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: From the Department of Laboratory Medicine, Division of Clinical Microbiology, F68, and.
authors.forename: João A
authors.initials: JA
authors.lastname: Paredes
authors.affiliation: From the Department of Laboratory Medicine, Division of Clinical Microbiology, F68, and.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: the Department of Laboratory Medicine, Division of Clinical Research Centre, Karolinska Institute, Karolinska University Hospital, SE-14186 Huddinge, Sweden.
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.affiliation: the Department of Laboratory Medicine, Division of Clinical Research Centre, Karolinska Institute, Karolinska University Hospital, SE-14186 Huddinge, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: From the Department of Laboratory Medicine, Division of Clinical Microbiology, F68, and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Curbo
authors.affiliation: From the Department of Laboratory Medicine, Division of Clinical Microbiology, F68, and anna.karlsson@ki.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009711:Nucleotides / Q000235:genetics / Q000378:metabolism*; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004272:DNA, Mitochondrial; D029721:Drosophila Proteins; D009711:Nucleotides; D010770:Phosphotransferases; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C021892:nucleoside phosphotransferase
keywords: Gene Therapy; Mitochondrial DNA (mtDNA); Mitochondrial Disease; Nucleoside/Nucleotide Metabolism; Nucleoside/Nucleotide Transport; Thymidine Kinase 2