Long term survival and abnormal liver fat accumulation in mice with specific thymidine kinase 2 deficiency in liver tissue

Abstract

Deficiency in thymidine kinase 2 (TK2) causes mitochondrial DNA depletion. Liver mitochondria are severely affected inTk2complete knockout models and have been suggested to play a role in the pathogenesis of theTk2knockout phenotype, characterized by loss of hypodermal fat tissue, growth retardation and reduced life span. Here we report a liver specificTk2knockout (KO) model to further study mechanisms contributing to the phenotypic changes associated withTk2deficiency. Interestingly, the liver specificTk2KO mice had a normal life span despite a much lower mtDNA level in liver tissue. Mitochondrial DNA encoded peptide COXI did not differ between theTk2KO and control mice. However, the relative liver weight was significantly increased in the maleTk2KO mouse model. Histology analysis indicated an increased lipid accumulation. We conclude that other enzyme activities can partly compensateTk2deficiency to maintain mtDNA at a low but stable level throughout the life span of the liver specificTk2KO mice. The lower level of mtDNA was sufficient for survival but led to an abnormal lipid accumulation in liver tissue.