Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
PLoS One. 2022 Jun 29;17(6):e0270418. doi: 10.1371/journal.pone.0270418. eCollection 2022.
Thymidine kinase 2 (TK2) deficiency in humans leads to a myopathic form of mitochondrial DNA (mtDNA) deficiency. Here we present a skeletal and cardiac muscle specific TK2 knockout mouse (mTk2 KO). The mice showed dilated hearts and markedly reduced adipose tissue during week 12 to 16. A severe decrease of mtDNA was found only in skeletal muscle and heart tissue in mTk2 KO mice. Expression analysis of key metabolic genes of 16 weeks knockout mice showed significant changes of genes involved in lipid metabolism, with different patterns in heart and skeletal muscle. Our study further suggests that lipoprotein lipase (LPL) from liver supports the metabolism when heart and skeletal muscle were impaired due to mitochondrial dysfunction. The angiotensin-converting enzyme 2 (ACE2), which is involved in glucose homeostasis, was also affected by mtDNA deficiency in our study. Interestingly, both the gene and protein expression of ACE2 were increased in cardiac tissue of mTk2 KO mice. Since ACE2 is a receptor for the SARS-CoV-2 virus, its regulation in relation to mitochondrial function may have important clinical implications.
人类胸苷激酶 2（TK2）缺陷导致线粒体 DNA（mtDNA）缺陷的肌病形式。在这里，我们介绍了一种骨骼肌和心肌特异性 TK2 敲除小鼠（mTk2 KO）。这些小鼠在 12 至 16 周时表现出心脏扩张和明显减少的脂肪组织。仅在 mTk2 KO 小鼠的骨骼肌和心肌组织中发现 mtDNA 严重减少。对 16 周龄敲除小鼠关键代谢基因的表达分析表明，涉及脂质代谢的基因发生了显著变化，心脏和骨骼肌的模式不同。我们的研究进一步表明，由于线粒体功能障碍导致心脏和骨骼肌受损时，来自肝脏的脂蛋白脂肪酶（LPL）支持代谢。血管紧张素转换酶 2（ACE2）参与葡萄糖稳态，在我们的研究中也受到 mtDNA 缺乏的影响。有趣的是，mTk2 KO 小鼠心脏组织中的 ACE2 基因和蛋白表达均增加。由于 ACE2 是 SARS-CoV-2 病毒的受体，因此其与线粒体功能的调节可能具有重要的临床意义。
