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Human Molecular Genetics Advance Access published online on April 22, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn133
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Progressive loss of mitochondrial DNA in thymidine kinase 2 deficient mice

Xiaoshan Zhou, Nicola Solaroli, Mia Bjerke, James B. Stewart, Björn Rozell, Magnus Johansson and Anna Karlsson*

Department of Laboratory Medicine, Karolinska Institute, S-141 86 Huddinge, Sweden

* Corresponding author:Dr. Anna Karlsson, Karolinska Institute, Department of Laboratory Medicine, F68, Karolinska University Hospital/ Huddinge, S-141 86 Huddinge, Sweden, Phone: +46-8-58580000, E-mail: anna.karlsson{at}ki.se

Received March 5, 2008; Revised April 18, 2008; Accepted April 18, 2008

Deficient enzymatic activity of the mitochondrial deoxyribonucleoside kinases deoxyguanosine kinase (DGUOK) or thymidine kinase 2 (TK2) cause mitochondrial DNA (mtDNA) depletion syndromes in humans. Here we report the generation of a Tk2 deficient mouse strain and show that the mice develop essentially normal for the first week but from then on exhibit growth retardation and die within the first weeks of life. Several organs including skeletal muscle, heart, liver and spleen showed progressive loss of mtDNA without increased mtDNA mutations or structural alterations. There were no major histological changes in skeletal muscle, but heart muscle showed disorganized and damaged muscle fibers. Electron microscopy showed mitochondria with distorted cristae. The Tk2 deficient mice exhibited pronounced hypothermia and showed loss of hypodermal fat and abnormal brown adipose tissue. We conclude that Tk2 has a major role in supplying deoxyribo-nucleotides for mtDNA replication and that other pathways of deoxyribonucleotide synthesis cannot compensate for loss of this enzyme.


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