title: Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.
abstract: Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.
authors.affiliation: Division of Clinical Microbiology F-68, Karolinska Institutet, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Zhou
authors.forename: Kristina
authors.initials: K
authors.lastname: Kannisto
authors.forename: Sophie
authors.initials: S
authors.lastname: Curbo
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Sindra
authors.initials: S
authors.lastname: Isetun
authors.forename: Mats
authors.initials: M
authors.lastname: Gåfvels
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002784:Cholesterol / Q000097:blood; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000648:ultrastructure; D010084:Oxidation-Reduction; D013937:Thymidine Kinase / Q000172:deficiency* / Q000235:genetics; D059467:Transcriptome
chemical_list: D004272:DNA, Mitochondrial; D005230:Fatty Acids, Nonesterified; C116917:acylcarnitine; D000255:Adenosine Triphosphate; D002784:Cholesterol; C105339:thymidine kinase 2; D013937:Thymidine Kinase; D002268:Carboxypeptidases; D002331:Carnitine