♦ See referenced article, J. Biol. Chem. 2013, 288, 5072–5079
Thymidine kinase 2 (TK2) is a salvage enzyme tasked with delivering a constant supply of deoxythymidine triphosphate (dTTP) to the mitochondria to maintain a balanced deoxyribonucleoside triphosphate (dNTP) pool and to support mitochondrial DNA replication and integrity. A deficiency in TK2 causes depletion of mtDNA, resulting in a number of devastating diseases. In this Paper of the Week, a team led by Anna Karlsson at the Karolinska Institute in Sweden reported a potential strategy for reversing the symptoms of TK2 deficiency in transgenic mice. The team expressed the nucleoside kinase from Drosophila melanogaster (Dm-dNK) in the cell nucleus of TK2-deficient mice, which compensated for the loss of mitochondrial deoxythymidine monophosphate (dTMP) synthesis in differentiated tissue. Ultimately, the mice displayed normal growth, behavior, and levels of mtDNA, opening the door to new potential therapies for TK2 deficiency.
Development and characterization of TK2-deficient mice expressing Dm-dNK (Dm-dNK+/− TK2−/−). A, establishment of the Dm-dNK+/−TK2−/− mice. B, genotyping of wt, Dm-dNK+/−, and Dm-dNK+/−TK2−/− mice (n = 2 each) by Southern blot using SpeI restriction enzyme. The detection of 6.9-kb DNA in lanes 5 and 6 confirms disruption of the TK2 gene in the mice. C, relative organ weight (organ weight/body weight) of the heart, liver, kidney, and spleen (%) of wt, Dm-dNK+/−, and Dm-dNK +/−TK2−/− mice (n = 3–6, mean ± S.E.). D, histological analysis of anterior straight femoral muscle and liver tissues from 6-month-old wt, Dm-dNK+/−, and Dm-dNK+/−TK2−/− mice (original magnification of each panel, ×20). Scale bars = 50 μm.