ER-mitochondria cross-talk is regulated by the Ca2+ sensor NCS1 and is impaired in Wolfram syndrome

The Ca2+ sensor NCS1 promotes ER-mitochondria contact and Ca2+ transfer between these organelles. The ER-mitochondria connection for Ca2+ Loss-of-function mutations in the ER protein WFS1 result in Wolfram syndrome; however, some of the defining symptoms of this disorder, such as diabetes and optic atrophy, are due to mitochondrial dysfunction. Using fibroblasts from Wolfram syndrome patients or normal individuals, Angebault et al. found that WFS1 deficiency was associated with decreased Ca2+ uptake by mitochondria, reduced mitochondrial contact with the ER, and decreased mitochondrial respiration. WFS1 interacted with a Ca2+-sensing protein, called NCS1, and NCS1 abundance was lower in patient fibroblasts than in control fibroblasts. Reconstituting NCS1 in patient fibroblasts restored mitochondrial respiration and Ca2+ signaling dynamics. These results explain how a deficiency in an ER protein impairs mitochondrial activity and suggest that defective ER-mitochondria association may contribute to the pathogenesis of neurodegenerative disorders. 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.