Human mtDNA sublimons resemble rearranged mitochondrial genoms found in pathological states
Human mtDNA sublimons resemble rearranged mitochondrial genoms found in pathological states
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DOI：
10.1093/hmg/9.19.2821
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发表时间：
2000-11-22
影响因子：
3.5
通讯作者：
Jacobs, HT
中科院分区：
文献类型：
--
作者：
Kajander, OA;Rovio, AT;Jacobs, HT
升华子最初在植物线粒体中发现，被定义为以非常低的水平存在的重排的mtDNA分子。我们分析了在人体细胞和组织中发现的升华子的初级结构，并估计了它们的丰度。给定个体的每个组织都含有大量不同的升华子，并且最丰富的种类以基本系统的方式在组织之间存在差异。在rho（0）细胞中检测不到升华子，表明它们是mtDNA的真正衍生物。它们在受到氧化应激的有丝分裂后组织中最突出。重排断点，通常由短的直接重复序列定义，是分散的，但热点区域是明确可识别的，特别是在D环末端附近。因此，复制起点之间的区域经常被消除。另一个热点区域位于蛋白质结合的已知位点附近，表明蛋白质-蛋白质相互作用可能促进重组。对于给定的一级重排，可以检测到缺失和部分重复的物种。虽然每个sublimon通常以低水平存在，每个细胞最多几个拷贝，但给定组织中的sublimon丰度在健康个体之间可以变化超过三个数量级。它们的结构与病理状态下发现的重排分子（如adPEO和MNGIE）非常相似;因此，我们提出，与植物一样，人类mtDNA升华子代表了一个在病理条件下可以扩增的变异分子库，从而导致细胞功能障碍。
Sublimons, originally identified in plant mitochondria, are defined as rearranged mtDNA molecules present at very low levels. We have analysed the primary structures of sublimons found in human cells and tissues and estimated their abundance. Each tissue of a given individual contains a wide range of different sublimons and the most abundant species differ between tissues in a substantially systematic manner, Sublimons are undetectable in rho (0) cells, indicating that they are bona fide derivatives of mtDNA, They are most prominent in postmitotic tissue subject to oxidative stress. Rearrangement break-points, often defined by short direct repeats, sire scattered, but hotspot regions are clearly identifiable, notably near the end of the D-loop, The region between the replication origins is therefore frequently eliminated, One other hotspot region is located adjacent to a known site of protein binding, suggesting that recombination may be facilitated by protein-protein interactions. For a given primary rearrangement, both deleted and partially duplicated species can be detected. Although each sublimon is typically present at a low level, at most a few copies per cell, sublimon abundance in a given tissue can vary over three orders of magnitude between healthy individuals. Collectively, therefore, they can represent a non-negligible fraction of total mtDNA, Their structures are very similar to those of the rearranged molecules found in pathological states, such as adPEO and MNGIE; therefore, we propose that, as in plants, human mtDNA sublimons represent a pool of variant molecules that can become amplified under pathological conditions, thus contributing to cellular dysfunction.