Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, FI 80101, Joensuu, Finland.
Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, FI 80101, Joensuu, Finland.
Mitochondrion. 2019 Jan;44:85-92. doi: 10.1016/j.mito.2018.01.004. Epub 2018 Jan 12.
The different cell types of multicellular organisms have specialized physiological requirements, affecting also their mitochondrial energy production and metabolism. The genome of mitochondria is essential for mitochondrial oxidative phosphorylation (OXHPOS) and thus plays a central role in many human mitochondrial pathologies. Disorders affecting mitochondrial DNA (mtDNA) maintenance are typically resulting in a tissue-specific pattern of mtDNA deletions and rearrangements. Despite this role in disease as well as a biomarker of mitochondrial biogenesis, the tissue-specific parameters of mitochondrial DNA maintenance have been virtually unexplored. In the presented study, we investigated mtDNA replication, topology, gene expression and damage in six different tissues of adult mice and sought to correlate these with the levels of known protein factors involved in mtDNA replication and transcription. Our results show that while liver and kidney cells replicate their mtDNA using the asynchronous mechanism known from cultured cells, tissues with high OXPHOS activity, such as heart, brain, skeletal muscle and brown fat, employ a strand-coupled replication mode, combined with increased levels of recombination. The strand-coupled replication mode correlated also with mtDNA damage levels, indicating that the replication mechanism represents a tissue-specific strategy to deal with intrinsic oxidative stress. While the preferred replication mode did not correlate with mtDNA transcription or the levels of most known mtDNA maintenance proteins, mtSSB was most abundant in tissues using strand-asynchronous mechanism. Although mitochondrial transcripts were most abundant in tissues with high metabolic rate, the mtDNA copy number per tissue mass was remarkably similar in all tissues. We propose that the tissue-specific features of mtDNA maintenance are primarily driven by the intrinsic reactive oxygen species exposure, mediated by DNA repair factors, whose identity remains to be elucidated.
多细胞生物的不同细胞类型具有专门的生理需求，这也影响了它们的线粒体能量产生和代谢。线粒体的基因组对于线粒体氧化磷酸化（OXHPOS）至关重要，因此在许多人类线粒体疾病中起着核心作用。影响线粒体 DNA（mtDNA）维持的疾病通常导致 mtDNA 缺失和重排的组织特异性模式。尽管在线粒体生物发生的标志物以及疾病中发挥着作用，但线粒体 DNA 维持的组织特异性参数实际上尚未得到探索。在本研究中，我们研究了成年小鼠的六种不同组织中线粒体 DNA 的复制、拓扑结构、基因表达和损伤，并试图将这些与已知参与 mtDNA 复制和转录的蛋白质因子的水平相关联。我们的结果表明，虽然肝和肾细胞使用已知的来自培养细胞的异步机制复制其 mtDNA，但具有高 OXPHOS 活性的组织，如心脏、大脑、骨骼肌和棕色脂肪，采用链偶联的复制模式，与增加的重组水平相结合。链偶联的复制模式也与 mtDNA 损伤水平相关，表明复制机制代表了一种组织特异性策略，用于应对内在的氧化应激。虽然首选的复制模式与 mtDNA 转录或大多数已知的 mtDNA 维持蛋白的水平没有相关性，但 mtSSB 在使用链异步机制的组织中最为丰富。尽管线粒体转录物在代谢率高的组织中最为丰富，但每个组织质量的 mtDNA 拷贝数在所有组织中都非常相似。我们提出，mtDNA 维持的组织特异性特征主要由内在活性氧物质暴露驱动，这是由 DNA 修复因子介导的，其身份仍有待阐明。
