Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland.
Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
Nucleic Acids Res. 2018 Oct 12;46(18):9625-9636. doi: 10.1093/nar/gky793.
Maintenance of topological homeostasis is vital for gene expression and genome replication in all organisms. Similar to other circular genomes, also mitochondrial DNA (mtDNA) is known to exist in various different topological forms, although their functional significance remains unknown. We report here that both known type II topoisomerases Top2α and Top2β are present in mammalian mitochondria, with especially Top2β regulating the supercoiling state of mtDNA. Loss of Top2β or its inhibition by ciprofloxacin results in accumulation of positively supercoiled mtDNA, followed by cessation of mitochondrial transcription and replication initiation, causing depletion of mtDNA copy number. These mitochondrial effects block both cell proliferation and differentiation, possibly explaining some of the side effects associated with fluoroquinolone antibiotics. Our results show for the first time the importance of topology for maintenance of mtDNA homeostasis and provide novel insight into the mitochondrial effects of fluoroquinolones.
维持拓扑动态平衡对于所有生物体的基因表达和基因组复制至关重要。与其他环状基因组类似，线粒体 DNA（mtDNA）也存在各种不同的拓扑形式，尽管其功能意义尚不清楚。我们在此报告，两种已知的 II 型拓扑异构酶 Top2α 和 Top2β 都存在于哺乳动物的线粒体中，特别是 Top2β 调节 mtDNA 的超螺旋状态。Top2β 的缺失或其被环丙沙星抑制会导致正超螺旋 mtDNA 的积累，随后线粒体转录和复制起始停止，导致 mtDNA 拷贝数耗竭。这些线粒体效应阻止了细胞增殖和分化，可能解释了与氟喹诺酮类抗生素相关的一些副作用。我们的结果首次表明拓扑结构对于维持 mtDNA 动态平衡的重要性，并为氟喹诺酮类药物的线粒体效应提供了新的见解。
