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首页> 外文期刊>Nucleus >Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates
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Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates

机译：Prelamin A的持续积累和Lamin A / C的消耗均会引起氧化应激和线粒体功能障碍，但会诱发不同的细胞命运

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摘要

The cell nucleus is structurally and functionally organized by lamins, intermediate filament proteins that form the nuclear lamina. Point mutations in genes that encode a specific subset of lamins, the A-type lamins, cause a spectrum of diseases termed laminopathies. Recent evidence points to a role for A-type lamins in intracellular redox homeostasis. To determine whether lamin A/C depletion and prelamin A accumulation differentially induce oxidative stress, we have performed a quantitative microscopy-based analysis of reactive oxygen species (ROS) levels and mitochondrial membrane potential ((m)) in human fibroblasts subjected to sustained siRNA-mediated knockdown of LMNA and ZMPSTE24, respectively. We measured a highly significant increase in basal ROS levels and an even more prominent rise of induced ROS levels in lamin A/C depleted cells, eventually resulting in (m)hyperpolarization and apoptosis. Depletion of ZMPSTE24 on the other hand, triggered a senescence pathway that was associated with moderately increased ROS levels and a transient (m)depolarization. Both knockdowns were accompanied by an upregulation of several ROS detoxifying enzymes. Taken together, our data suggest that both persistent prelamin A accumulation and lamin A/C depletion elevate ROS levels, but to a different extent and with different effects on cell fate. This may contribute to the variety of disease phenotypes witnessed in laminopathies.
机译：细胞核在结构上和功能上都由lamins（形成核层的中间细丝蛋白）组成。编码lamin的特定子集（A型lamin）的基因中的点突变会引起一系列疾病，称为lamopathies。最近的证据表明A型lamin在细胞内氧化还原稳态中的作用。为了确定lamin A / C消耗和prelamin A积累是否差异诱导氧化应激，我们已经进行了基于显微镜的定量化学分析，研究了经过持续siRNA作用的人成纤维细胞中活性氧（ROS）水平和线粒体膜电位（（m））介导的LMNA和ZMPSTE24的敲低。我们测量了薄层A / C耗尽细胞中基础ROS水平的显着增加以及诱导ROS水平的显着升高，最终导致（m）超极化和细胞凋亡。另一方面，ZMPSTE24的耗尽会触发衰老途径，该途径与ROS水平适度增加和短暂的（m）去极化有关。两种击倒都伴随着几种ROS解毒酶的上调。两者合计，我们的数据表明持久的prelamin A积累和lamin A / C消耗都提高了ROS水平，但程度不同，对细胞命运的影响也不同。这可能会导致在椎间盘突出症中表现出多种疾病表型。

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