Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
PLoS One. 2023 Oct 5;18(10):e0285242. doi: 10.1371/journal.pone.0285242. eCollection 2023.
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.
胸苷激酶 2（TK2）缺乏可导致线粒体 DNA 耗竭。Tk2 完全敲除模型中的肝线粒体受到严重影响，据推测其在 Tk2 敲除表型的发病机制中起作用，该表型的特征是皮下脂肪组织丧失、生长迟缓以及寿命缩短。在这里，我们报告了一种肝脏特异性 Tk2 敲除（KO）模型，以进一步研究与 Tk2 缺乏相关的表型变化的机制。有趣的是，尽管肝组织中的 mtDNA 水平低得多，但肝脏特异性 Tk2 KO 小鼠的寿命正常。线粒体 DNA 编码的肽 COXI 在 Tk2 KO 和对照小鼠之间没有差异。然而，雄性 Tk2 KO 小鼠模型的相对肝重显著增加。组织学分析表明脂质积累增加。我们的结论是，其他酶活性可以部分补偿 Tk2 缺乏，以在肝脏特异性 Tk2 KO 小鼠的整个生命周期内将 mtDNA 维持在低但稳定的水平。较低水平的 mtDNA 足以存活，但导致肝组织中异常的脂质积累。
