title: Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice.
abstract: 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 normally for the first week but from then on exhibit growth retardation and die within 2-4 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 deoxyribonucleotides for mtDNA replication and that other pathways of deoxyribonucleotide synthesis cannot compensate for loss of this enzyme.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institute, S-141 86 Huddinge, Sweden.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Zhou
authors.forename: Nicola
authors.initials: N
authors.lastname: Solaroli
authors.forename: Mia
authors.initials: M
authors.lastname: Bjerke
authors.forename: James B
authors.initials: JB
authors.lastname: Stewart
authors.forename: Björn
authors.initials: B
authors.lastname: Rozell
authors.forename: Magnus
authors.initials: M
authors.lastname: Johansson
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D006130:Growth Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008060:Lipodystrophy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009711:Nucleotides / Q000096:biosynthesis; D013937:Thymidine Kinase / Q000235:genetics / Q000502:physiology*
chemical_list: D004272:DNA, Mitochondrial; D009711:Nucleotides; C105339:thymidine kinase 2; D013937:Thymidine Kinase