mTORC1 inhibitor rapamycin and ER stressor tunicamycin induce differential patterns of ER-mitochondria coupling.
mTORC1 inhibitor rapamycin and ER stressor tunicamycin induce differential patterns of ER-mitochondria coupling.
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DOI：
10.1038/srep36394
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发表时间：
2016-11-03
影响因子：
4.6
通讯作者：
Lavandero S
中科院分区：
文献类型：
--
作者：
Bravo-Sagua R;López-Crisosto C;Parra V;Rodriguez-Peña M;Rothermel BA;Quest AF;Lavandero S
有效的线粒体钙摄取发生在内质网和线粒体之间的接触点，是许多细胞功能的关键调节因子。在之前对HeLa细胞的研究中，我们发现在衣霉素诱导的内质网应激的早期阶段，内质网到线粒体的钙离子转移增加，这是一种刺激线粒体生物能量学的适应性反应。目前尚不清楚其他类型的压力信号是否会引发类似的反应。在这里，我们观察到雷帕霉素，它抑制营养感知复合体mTORC1，增加了HeLa细胞中ER-线粒体的偶联，其程度与衣霉素相似。有趣的是，尽管全球对这两种压力源的反应具有可比性，但这种变化的空间分布存在显著差异。衣霉素增加了细胞器的接近，主要是在核周区域，而雷帕霉素增加了整个细胞的细胞器接触。与这些差异平行的是，内质网-线粒体界面调节蛋白分布的不同变化，线粒体钙摄取的异质性，以及线粒体网络中具有不同线粒体跨膜电位的结构域的形成。总之，这些数据表明，虽然增加内质网-线粒体耦合似乎代表了对细胞应激的一般反应，但相关反应的细胞内分布需要量身定做，以满足特定的细胞要求。
Efficient mitochondrial Ca2+ uptake takes place at contact points between the ER and mitochondria, and represents a key regulator of many cell functions. In a previous study with HeLa cells, we showed that ER-to-mitochondria Ca2+ transfer increases during the early phase of ER stress induced by tunicamycin as an adaptive response to stimulate mitochondrial bioenergetics. It remains unknown whether other types of stress signals trigger similar responses. Here we observed that rapamycin, which inhibits the nutrient-sensing complex mTORC1, increased ER-mitochondria coupling in HeLa cells to a similar extent as did tunicamycin. Interestingly, although global responses to both stressors were comparable, there were notable differences in the spatial distribution of such changes. While tunicamycin increased organelle proximity primarily in the perinuclear region, rapamycin increased organelle contacts throughout the entire cell. These differences were paralleled by dissimilar alterations in the distribution of regulatory proteins of the ER-mitochondria interface, heterogeneities in mitochondrial Ca2+ uptake, and the formation of domains within the mitochondrial network with varying mitochondrial transmembrane potential. Collectively, these data suggest that while increasing ER-mitochondria coupling appears to represent a general response to cell stress, the intracellular distribution of the associated responses needs to be tailored to meet specific cellular requirements.