High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo.
High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo.
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DOI：
10.26508/lsa.202101034
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发表时间：
2021-11
影响因子：
4.4
通讯作者：
Larsson NG
中科院分区：
文献类型：
--
作者：
Bonekamp NA;Jiang M;Motori E;Garcia Villegas R;Koolmeister C;Atanassov I;Mesaros A;Park CB;Larsson NG
TFAM与mtDNA的比例至关重要，必须保持在生理范围内，以允许正常的mtDNA表达，并防止不同小鼠组织中的类核超致密化。线粒体转录因子A（TFAM）是将线粒体DNA（dmtDNA）压缩成类核并直接控制mtDNA拷贝数的重要因子。在这里，我们表明，TFAM-mtDNA的比例是至关重要的，在不同的小鼠组织中维持正常的mtDNA表达。TFAM蛋白水平的适度增加会增加mtDNA的拷贝数，但保持正常的TFAM与mtDNA的比例，导致mtDNA表达不变和整个动物的正常代谢。普遍表达非常高的TFAM水平的小鼠发展出导致氧化磷酸化缺陷（OXPHOS）和出生后早期致死的病理学。TFAM与mtDNA的比率在这些小鼠的组织之间变化很大，并且在骨骼肌中非常高，导致mtDNA表达的强烈抑制和OXPHOS缺乏。在心脏中，增加的mtDNA拷贝数导致接近正常的TFAM与mtDNA比率并维持OXPHOS能力。在肝脏中，LONP 1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。TFAM因此作为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。
The TFAM-to-mtDNA ratio is critically important and must be maintained within a physiological range to allow normal mtDNA expression and prevent nucleoid hypercompaction in different mouse tissues. 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.