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Long term survival and abnormal liver fat accumulation in mice with specific thymidine kinase 2 deficiency in liver
Qian Zhao1, Xiaoshan Zhou1, Jingyi Yan1
1Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Abstract:
Deficiency in thymidine kinase 2 (TK2) causes mitochondrial DNA depletion. Liver mitochondria are severely affected in Tk2 complete knockout models and have been suggested to play a role in the pathogenesis of the Tk2 knockout phenotype, characterized by loss of hypodermal fat tissue, growth retardation and reduced life span. Here we report a liver specific Tk2 knockout (KO) model to further study mechanisms contributing to the phenotypic changes associated with Tk2 deficiency. Interestingly, the liver specific Tk2 KO mice had a normal life span despite a much lower mtDNA level in liver tissue. Mitochondrial DNA encoded peptide COXI did not differ between the Tk2 KO and control mice. However, the relative liver weight was significantly increased in the male Tk2 KO mouse model. Histology analysis indicated an increased lipid accumulation. We conclude that other enzyme activities can partly compensate Tk2 deficiency to maintain mtDNA at a low but stable level throughout the life span of the liver specific Tk2 KO mice. The lower level of mtDNA was sufficient for survival but led to an abnormal lipid accumulation in liver tissue.
Insights
Thymidine kinase 2 (TK2) deficiency causes mitochondrial DNA depletion. Liver-specific TK2 knockout mice show normal lifespan despite low mtDNA, but develop abnormal lipid accumulation in the liver.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Thymidine kinase 2 (TK2) deficiency leads to mitochondrial DNA (mtDNA) depletion.
- TK2 knockout models exhibit severe liver issues, impacting phenotypes like growth and lifespan.
- The role of liver mitochondria in TK2 deficiency pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the mechanisms behind phenotypic changes in TK2 deficiency using a liver-specific knockout model.
- To assess the impact of liver-specific TK2 deficiency on mtDNA levels, lifespan, and liver pathology.
Main Methods:
- Generation of a liver-specific Tk2 knockout (KO) mouse model.
- Analysis of mtDNA levels in liver tissue.
- Assessment of mitochondrial DNA-encoded peptide COXI levels.
- Measurement of relative liver weight and histological examination for lipid accumulation.
Main Results:
- Liver-specific Tk2 KO mice maintained a normal lifespan despite significantly reduced liver mtDNA levels.
- No significant difference in COXI peptide levels was observed between KO and control mice.
- Male Tk2 KO mice exhibited increased relative liver weight and significant lipid accumulation, indicating hepatic steatosis.
Conclusions:
- Compensatory enzyme activities can maintain a stable, albeit low, level of mtDNA in the absence of TK2 in the liver.
- Reduced mtDNA levels are compatible with survival but result in abnormal lipid accumulation in liver tissue.
- This model elucidates the specific role of liver TK2 in maintaining metabolic homeostasis and preventing hepatic lipidosis.
