Mitochondrial transcription factor A (TFAM) is compacting mitochondrial DNA (dmtDNA) into nucleoids and directly controls mtDNA copy number. Here, we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different mouse tissues. Moderately increased TFAM protein levels increase mtDNA copy number but a normal TFAM-to-mtDNA ratio is maintained resulting in unaltered mtDNA expression and normal whole animal metabolism. Mice ubiquitously expressing very high TFAM levels develop pathology leading to deficient oxidative phosphorylation (OXPHOS) and early postnatal lethality. The TFAM-to-mtDNA ratio varies widely between tissues in these mice and is very high in skeletal muscle leading to strong repression of mtDNA expression and OXPHOS deficiency. In the heart, increased mtDNA copy number results in a near normal TFAM-to-mtDNA ratio and maintained OXPHOS capacity. In liver, induction of LONP1 protease and mitochondrial RNA polymerase expression counteracts the silencing effect of high TFAM levels. TFAM thus acts as a general repressor of mtDNA expression and this effect can be counterbalanced by tissue-specific expression of regulatory factors.

中文翻译：

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高水平的 TFAM 在体内抑制哺乳动物线粒体 DNA 转录。

线粒体转录因子 A (TFAM) 将线粒体 DNA (dmtDNA) 压缩成类核并直接控制 mtDNA 拷贝数。在这里，我们表明 TFAM 与 mtDNA 的比率对于维持不同小鼠组织中正常的 mtDNA 表达至关重要。适度增加的 TFAM 蛋白水平会增加 mtDNA 拷贝数，但维持正常的 TFAM 与 mtDNA 的比率，导致 mtDNA 表达不变和整个动物代谢正常。普遍表达非常高 TFAM 水平的小鼠会发展导致氧化磷酸化 (OXPHOS) 缺陷和出生后早期致死率的病理。这些小鼠组织之间的 TFAM 与 mtDNA 比率差异很大，并且在骨骼肌中非常高，导致 mtDNA 表达受到强烈抑制和 OXPHOS 缺乏。在心里，增加的 mtDNA 拷贝数导致 TFAM 与 mtDNA 的比例接近正常，并保持 OXPHOS 容量。在肝脏中，LONP1 蛋白酶和线粒体 RNA 聚合酶表达的诱导抵消了高 TFAM 水平的沉默效应。因此，TFAM 作为 mtDNA 表达的一般阻遏物，这种作用可以通过调节因子的组织特异性表达来抵消。