Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation
Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation
复制标题
DOI：
10.1093/hmg/ddq453
复制
发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Hirano, Michio
中科院分区：
文献类型：
--
作者：
Dorado, Beatriz;Area, Estela;Hirano, Michio
胸苷激酶2（TK 2）缺乏是线粒体DNA（mtDNA）缺失的儿童孤立性肌病或脑肌病的常见原因。为了确定TK 2缺陷的发病基础、器官特异性和严重性，我们仔细表征了Tk 2 H126 N敲入小鼠（Tk 2（-/-））。尽管Tk 2（-/-）小鼠在出生后第8天之前都是正常的，但在出生后第10天和第13天之间迅速发生致命性脑肌病。我们已经观察到野生型Tk 2活性在生命的第二周是恒定的，而Tk 1活性在出生后第8天和第13天之间显著降低。Tk 1活性的下调揭示了Tk 2（-/-）小鼠中Tk 2的缺陷，并与脑和心脏中mtDNA耗竭的发生相关。Tk 2突变器官对病理的抵抗取决于对减少的mtDNA水平的补偿机制。我们在出生后第13天的分析表明，Tk 2（-/-）心脏显着增加线粒体转录水平相对于mtDNA含量。这种转录补偿允许心脏维持正常水平的mtDNA编码蛋白。线粒体转录本的上调不是由于主要线粒体生物发生调节剂过氧化物酶体增殖物激活受体-γ共激活因子1 α和核呼吸因子1和2的表达增加，也不是由于线粒体转录因子A、B1或B2的表达增强。相反，Tk 2（-/-）心脏通过下调线粒体转录终止子转录因子3（MTERF 3）的表达来补偿mtDNA的缺失。了解允许Tk 2突变器官幸免的分子机制可能有助于设计Tk 2缺陷的治疗方法。
Deficiency of thymidine kinase 2 (TK2) is a frequent cause of isolated myopathy or encephalomyopathy in children with mitochondrial DNA (mtDNA) depletion. To determine the bases of disease onset, organ specificity and severity of TK2 deficiency, we have carefully characterized Tk2 H126N knockin mice (Tk2(-/-)). Although normal until postnatal day 8, Tk2(-/-) mice rapidly develop fatal encephalomyopathy between postnatal days 10 and 13. We have observed that wild-type Tk2 activity is constant in the second week of life, while Tk1 activity decreases significantly between postnatal days 8 and 13. The down-regulation of Tk1 activity unmasks Tk2 deficiency in Tk2(-/-) mice and correlates with the onset of mtDNA depletion in the brain and the heart. Resistance to pathology in Tk2 mutant organs depends on compensatory mechanisms to the reduced mtDNA level. Our analyses at postnatal day 13 have revealed that Tk2(-/-) heart significantly increases mitochondrial transcript levels relative to the mtDNA content. This transcriptional compensation allows the heart to maintain normal levels of mtDNA-encoded proteins. The up-regulation in mitochondrial transcripts is not due to increased expression of the master mitochondrial biogenesis regulators peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and nuclear respiratory factors 1 and 2, or to enhanced expression of the mitochondrial transcription factors A, B1 or B2. Instead, Tk2(-/-) heart compensates for mtDNA depletion by down-regulating the expression of the mitochondrial transcriptional terminator transcription factor 3 (MTERF3). Understanding the molecular mechanisms that allow Tk2 mutant organs to be spared may help design therapies for Tk2 deficiency.