Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ 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 (IP3R) to promote Ca2+ 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 Ca2+ exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca2+ 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.

中文翻译：

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ER-线粒体的串扰受Ca2 +传感器NCS1的调节，在Wolfram综合征中受损。

内质网（ER）与线粒体之间的通讯在Ca2 +信号传导，能量代谢和细胞存活中起着关键作用。这种串扰的功能障碍会导致代谢性疾病和神经退行性疾病。Wolfram综合征是一种致命的神经退行性疾病，由ER驻留蛋白WFS1的突变引起。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（IP3R）形成了复合物，以促进ER与线粒体之间的Ca2 +转移。此外，我们发现WFS1空患者成纤维细胞中NCS1丰度降低，这表明ER-线粒体相互作用和Ca2 +交换降低。此外，在WFS1缺失的细胞中，NCS1的过表达不仅恢复了ER-线粒体相互作用和Ca2 +转移，而且还挽救了线粒体功能障碍。