Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation.
Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation.
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DOI：
10.1186/s12915-022-01498-7
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发表时间：
2023-01-04
期刊：
影响因子：
5.4
通讯作者：
Bellesi, Michele
中科院分区：
文献类型：
--
作者：
El Alaoui, Amina Aboufares;Buhl, Edgar;Galizia, Sabrina;Hodge, James J. L.;de Vivo, Luisa;Bellesi, Michele
长时间的细胞活动可能使细胞功能超负荷，导致蛋白质合成的高速率和错误折叠或未组装的蛋白质的积累，这引起内质网（ER）应激并激活未折叠蛋白质反应（UPR）以重建正常的蛋白质稳态。先前的分子工作已经证明，睡眠剥夺（SD）导致神经元中的ER应激，许多ER特异性蛋白被上调以维持最佳的细胞蛋白质稳态。目前尚不清楚哪些细胞过程被睡眠剥夺激活导致ER-应激，但细胞代谢增加、蛋白质合成的更高要求和氧自由基的过度产生已被认为是潜在的促成因素。在这里，我们调查的转录和超微结构的ER和线粒体的修改引起的睡眠不足。我们使用小鼠前脑的基因表达分析表明，SD与ER应激相关基因的显著转录修饰有关，但也与ER-线粒体相互作用、钙稳态和线粒体呼吸活性相关。使用电子显微镜，我们还表明，SD与运动皮层锥体神经元中ER池密度的普遍增加有关。此外，ER池与线粒体建立了新的接触位点，即所谓的线粒体相关膜（MAMs），其是分子穿梭（如钙和脂质）以及调节ATP产生和氧化还原状态的重要枢纽。最后，我们证明了果蝇雄性突变果蝇（elav > linker），其中MAMs的数量已经遗传增加，显示睡眠量减少和巩固，而不改变稳态睡眠对SD的反应。我们提供的证据表明，睡眠不足会导致ER应激，其特征是ER和线粒体之间的串扰增加。与SD相关的MAMs形成可能代表了调节多个细胞过程的关键现象，这些过程确保对增加的细胞代谢的适当反应。此外，MAMs的建立可能在基线条件下的睡眠调节中发挥作用。在线版本包含补充材料，可通过10.1186/s12915-022-01498-7获得。
Prolonged cellular activity may overload cell function, leading to high rates of protein synthesis and accumulation of misfolded or unassembled proteins, which cause endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) to re-establish normal protein homeostasis. Previous molecular work has demonstrated that sleep deprivation (SD) leads to ER stress in neurons, with a number of ER-specific proteins being upregulated to maintain optimal cellular proteostasis. It is still not clear which cellular processes activated by sleep deprivation lead to ER- stress, but increased cellular metabolism, higher request for protein synthesis, and over production of oxygen radicals have been proposed as potential contributing factors. Here, we investigate the transcriptional and ultrastructural ER and mitochondrial modifications induced by sleep loss. We used gene expression analysis in mouse forebrains to show that SD was associated with significant transcriptional modifications of genes involved in ER stress but also in ER-mitochondria interaction, calcium homeostasis, and mitochondrial respiratory activity. Using electron microscopy, we also showed that SD was associated with a general increase in the density of ER cisternae in pyramidal neurons of the motor cortex. Moreover, ER cisternae established new contact sites with mitochondria, the so-called mitochondria associated membranes (MAMs), important hubs for molecule shuttling, such as calcium and lipids, and for the modulation of ATP production and redox state. Finally, we demonstrated that Drosophila male mutant flies (elav > linker), in which the number of MAMs had been genetically increased, showed a reduction in the amount and consolidation of sleep without alterations in the homeostatic sleep response to SD. We provide evidence that sleep loss induces ER stress characterized by increased crosstalk between ER and mitochondria. MAMs formation associated with SD could represent a key phenomenon for the modulation of multiple cellular processes that ensure appropriate responses to increased cell metabolism. In addition, MAMs establishment may play a role in the regulation of sleep under baseline conditions. The online version contains supplementary material available at 10.1186/s12915-022-01498-7.
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影响因子：
--
作者：
Armengol S;Arretxe E;Enzunza L;Mula S;Ochoa B;Chico Y;Martínez MJ
通讯作者：
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影响因子：
9.8
作者：
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4.2
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影响因子：
5.1
作者：
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通讯作者：
Kékesi KA