Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, 34090 Montpellier, France.
PhyMedExp, University of Montpellier, INSERM, CNRS, CHRU Montpellier, 34295 Montpellier, France.
Sci Signal. 2018 Oct 23;11(553):eaaq1380. doi: 10.1126/scisignal.aaq1380.
Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IPR) to promote Ca transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.
内质网（ER）和线粒体之间的通讯在 Ca 信号转导、能量代谢和细胞存活中起着关键作用。这种交流的功能障碍会导致代谢和神经退行性疾病。Wolfram 综合征是一种由 ER 驻留蛋白 WFS1 突变引起的致命神经退行性疾病。在这里，我们表明 WFS1 与神经元钙传感器 1（NCS1）和肌醇 1,4,5-三磷酸受体（IPR）形成复合物，以促进 ER 和线粒体之间的 Ca 转移。此外，我们发现 WFS1 缺失患者成纤维细胞中的 NCS1 丰度降低，这表明 ER-线粒体相互作用和 Ca 交换减少。此外，在 WFS1 缺陷细胞中，NCS1 的过表达不仅恢复了 ER-线粒体相互作用和 Ca 转移，而且还挽救了线粒体功能障碍。我们的研究结果描述了 NCS1 在 ER-线粒体通讯中的关键作用，揭示了 Wolfram 综合征的发病机制，并可能为其他神经退行性疾病的发病机制提供了新的见解。
