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

Claire Angebault 1, 2 Jérémy Fauconnier 2 Simone Patergnani 3 Jennifer Rieusset 4 Alberto Danese 3 Corentin Affortit 1 Jolanta Jagodzinska 1 Camille Mégy 1 Melanie Quilès 1 Chantal Cazevieille 1 Julia Korchagina 1 Delphine Bonnet-Wersinger 1 Dan Milea 5, 6 Christian Hamel 1, 7 Paolo Pinton 3 Marc Thiry 8 Alain Lacampagne 2 Benjamin Delprat 1, 9, * Cécile Delettre 1, *
* Corresponding author
1 INM - Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs
2 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
3 University of Ferrara [Ferrara]
4 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
5 Service d'ophtalmologie [Angers]
6 SERI - Singapore Eye Research Institute [Singapore]
7 Centre de référence pour les maladies génétiques sensorielles [CHRU Montpellier]
8 GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège]
9 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
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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Claire Angebault, Jérémy 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, 2018, 11 (553), pp.eaaq1380. ⟨10.1126/scisignal.aaq1380⟩. ⟨inserm-02380043⟩

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