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ER-mitochondria cross-talk is regulated by the Ca 2+ sensor NCS1 and is impaired in Wolfram syndrome

Abstract : 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.
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Submitted on : Tuesday, November 26, 2019 - 9:38:20 AM
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Claire Angebault, J. Fauconnier, Simone Patergnani, Jennifer Rieusset, Alberto Danese, et al.. ER-mitochondria cross-talk is regulated by the Ca 2+ sensor NCS1 and is impaired in Wolfram syndrome. Science Signaling, American Association for the Advancement of Science (AAAS), 2018, 11 (553), pp.eaaq1380. ⟨10.1126/scisignal.aaq1380⟩. ⟨inserm-02380043⟩



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