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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Ear, Inner / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria / metabolism*
  • Neuronal Calcium-Sensor Proteins / metabolism*
  • Neurons / metabolism
  • Neuropeptides / metabolism*
  • Oxygen Consumption
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Wolfram Syndrome / metabolism*

Substances

  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • RNA, Small Interfering
  • frequenin calcium sensor proteins
  • Calcium