Angebault 2018 Sci Signal
|Angebault C, Fauconnier J, Patergnani S, Rieusset J, Danese A, Affortit CA, Jagodzinska J, Mégy C, Quiles M, Cazevieille C, Korchagina J, Bonnet-Wersinger D, Milea D, Hamel C, Pinton P, Thiry M, Lacampagne A, Delprat B, Delettre C (2018) ER-mitochondria cross-talk is regulated by the Ca2+ sensor NCS1 and is impaired in Wolfram syndrome. Sci Signal 11:eaaq1380.|
Angebault C, Fauconnier J, Patergnani S, Rieusset J, Danese A, Affortit CA, Jagodzinska J, Megy C, Quiles M, Cazevieille C, Korchagina J, Bonnet-Wersinger D, Milea D, Hamel C, Pinton P, Thiry M, Lacampagne A, Delprat B, Delettre C (2018) Sci Signal
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.
Labels: MiParea: Respiration Pathology: Inherited, Neurodegenerative
Organism: Human Tissue;cell: Fibroblast Preparation: Permeabilized cells Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex IV;cytochrome c oxidase Regulation: Calcium, Ion;substrate transport Coupling state: LEAK, OXPHOS Pathway: N, S, NS HRR: Oxygraph-2k