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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

1
Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, 34090 Montpellier, France.
2
PhyMedExp, University of Montpellier, INSERM, CNRS, CHRU Montpellier, 34295 Montpellier, France.
3
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.
4
Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy.
5
INSERM U1060, UMR INRA 1397, CarMeN Laboratory, Lyon 1 University, F-69003 Lyon, France.
6
Department of Ophthalmology, Angers University Hospital, 43933 Angers, France.
7
Singapore Eye Research Institute, Duke-NUS Graduate Medical School, 169857 Singapore, Singapore.
8
CHRU Montpellier, Centre of Reference for Genetic Sensory Diseases, CHU, Gui de Chauliac Hospital, 34090 Montpellier, France.
9
Laboratoire de Biologie Cellulaire, Université de Liège, Bât. B36 (Tour 4) GIGA-Neurosciences, Quartier Hôpital, Avenue Hippocrate 15, 4000 Liège 1, Belgium.
10
Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, 34090 Montpellier, France. cecile.delettre@inserm.fr benjamin.delprat@inserm.fr.
11
MMDN, Univ. Montpellier, EPHE, INSERM U1198, F-34095 Montpellier, France.

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.

PMID:
30352948
DOI:
10.1126/scisignal.aaq1380

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