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Sci Signal. 2018 Oct 23;11(553). pii: eaaq1380. doi: 10.1126/scisignal.aaq1380.

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

Author information

Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, 34090 Montpellier, France.
PhyMedExp, University of Montpellier, INSERM, CNRS, CHRU Montpellier, 34295 Montpellier, France.
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.
Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy.
INSERM U1060, UMR INRA 1397, CarMeN Laboratory, Lyon 1 University, F-69003 Lyon, France.
Department of Ophthalmology, Angers University Hospital, 43933 Angers, France.
Singapore Eye Research Institute, Duke-NUS Graduate Medical School, 169857 Singapore, Singapore.
CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital, 34090 Montpellier, France.
Laboratoire de Biologie Cellulaire, Université de Liège, Bât. B36 (Tour 4) GIGA-Neurosciences, Quartier Hôpital, Avenue Hippocrate 15, 4000 Liège 1, Belgium.
Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, 34090 Montpellier, France.
MMDN, Univ. Montpellier, EPHE, INSERM U1198, F-34095 Montpellier, France.


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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