a MPRG Graef, Max Planck Institute for Biology of Ageing , Cologne , Germany.
b Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) , University of Cologne , Cologne , Germany.
Autophagy. 2019 Jan;15(1):178-179. doi: 10.1080/15548627.2018.1532263. Epub 2018 Oct 13.
Derived from bacterial ancestors, mitochondria have maintained their own albeit strongly reduced genome, mitochondrial DNA (mtDNA), which encodes for a small and highly specialized set of genes. MtDNA exists in tens to thousands of copies packaged in numerous nucleoprotein complexes, termed nucleoids, distributed throughout the dynamic mitochondrial network. Our understanding of the mechanisms of how cells regulate the copy number of mitochondrial genomes has been limited. Here, we summarize and discuss our recent findings that Mip1/POLG (mitochondrial DNA polymerase gamma) critically controls mtDNA copy number by operating in 2 opposing modes, synthesis and, unexpectedly, degradation of mtDNA, when yeast cells face nutrient starvation. The balance of the 2 modes of Mip1/POLG and thus mtDNA copy number dynamics depends on the integrity of macroautophagy/autophagy, which sustains continuous synthesis and maintenance of mtDNA. In autophagy-deficient cells, a combination of nucleotide insufficiency and elevated mitochondrial ROS production impairs mtDNA synthesis and drives mtDNA degradation by the 3'-5'-exonuclease activity of Mip1/POLG resulting in mitochondrial genome depletion and irreversible respiratory deficiency. Abbrivations: mtDNA: mitochondrial DNA; mtDCN: mitochondrial DNA copy number.
线粒体起源于细菌祖先，保留了自己的基因组，尽管这个基因组大大缩小了，称为线粒体 DNA（mtDNA），它编码一小部分高度特化的基因。mtDNA 以数十到数千个拷贝的形式存在，包装在许多核蛋白复合物中，称为核体，分布在动态的线粒体网络中。我们对细胞调节线粒体基因组拷贝数的机制的理解一直受到限制。在这里，我们总结并讨论了我们最近的发现，即 Mip1/POLG（线粒体 DNA 聚合酶 γ）通过两种相反的模式发挥作用，即 mtDNA 的合成和（出乎意料的是）降解，来控制 mtDNA 拷贝数，当酵母细胞面临营养饥饿时。Mip1/POLG 的两种模式的平衡，即 mtDNA 拷贝数的动态平衡，取决于巨自噬/自噬的完整性，它维持 mtDNA 的连续合成和维持。在自噬缺陷的细胞中，核苷酸不足和线粒体 ROS 产生增加的组合会损害 mtDNA 的合成，并通过 Mip1/POLG 的 3'-5'-外切酶活性驱动 mtDNA 降解，导致线粒体基因组耗竭和不可逆的呼吸缺陷。缩写：mtDNA：线粒体 DNA；mtDCN：线粒体 DNA 拷贝数。
