Prevalent coordination of mitochondrial DNA transcription and initiation of replication with the cell cycle
Prevalent coordination of mitochondrial DNA transcription and initiation of replication with the cell cycle
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DOI：
10.1093/nar/gkt015
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发表时间：
2013-03-01
影响因子：
14.9
通讯作者：
Ricchetti, Miria
中科院分区：
文献类型：
--
作者：
Chatre, Laurent;Ricchetti, Miria
细胞核（nDNA）和线粒体DNA（mtDNA）的通讯对细胞功能至关重要，但目前尚不清楚这些基因组的复制是否相关。我们检查了人类细胞与一种新的荧光原位杂交协议（线粒体转录和复制成像协议），确定参与启动mtDNA复制和独特的转录谱的线粒体结构，并重建在细胞周期中的单细胞线粒体和核事件的时间序列。我们发现，线粒体DNA的转录和复制的启动是prehistorically协调与细胞周期，核DNA合成之前，并被重新激活对S期结束。这种协调是通过调节启动mtDNA合成和/或在给定时间包含转录物的线粒体结构的部分来实现的。因此，尽管线粒体基因组的复制在整个细胞周期中是活跃的，但在线粒体结构的有限部分中，这些活动的峰值与nDNA合成同步。释放后，无论是诺考达唑或双胸苷治疗的mtDNA复制的封锁，普遍的mtDNA和nDNA合成同时发生，表明线粒体协调与核相可以调整，以响应生理变化。这些发现将有助于重新定义细胞功能中的其他核-线粒体联系。
Nuclear (nDNA) and mitochondrial DNA (mtDNA) communication is essential for cell function, but it remains unclear whether the replication of these genomes is linked. We inspected human cells with a novel fluorescence in situ hybridization protocol (mitochondrial Transcription and Replication Imaging Protocol) that identifies mitochondrial structures engaged in initiation of mtDNA replication and unique transcript profiles, and reconstruct the temporal series of mitochondrial and nuclear events in single cells during the cell cycle. We show that mtDNA transcription and initiation of replication are prevalently coordinated with the cell cycle, preceding nuclear DNA synthesis, and being reactivated towards the end of S-phase. This coordination is achieved by modulating the fraction of mitochondrial structures that intiate mtDNA synthesis and/or contain transcript at a given time. Thus, although replication of the mitochondrial genome is active through the entire cell cycle, but in a limited fraction of mitochondrial structures, peaks of these activities are synchronized with nDNA synthesis. After release from blockage of mtDNA replication with either nocodazole or double thymidine treatment, prevalent mtDNA and nDNA synthesis occurred simultaneously, indicating that mitochondrial coordination with the nuclear phase can be adjusted in response to physiological alterations. These findings will help redefine other nuclear-mitochondrial links in cell function.