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

2018 ◽  
Vol 11 (553) ◽  
pp. eaaq1380 ◽  
Author(s):  
Claire Angebault ◽  
Jérémy Fauconnier ◽  
Simone Patergnani ◽  
Jennifer Rieusset ◽  
Alberto Danese ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Energy Metabolism ◽  
Neurodegenerative Diseases ◽  
Cell Survival ◽  
Cross Talk ◽  
Wolfram Syndrome ◽  
Calcium Sensor ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

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.

IP3R, store-operated Ca2+ entry and neuronal Ca2+ homoeostasis in Drosophila

2012 ◽  
Vol 40 (1) ◽  
pp. 279-281 ◽  
Author(s):  
Sumita Chakraborty ◽  
Gaiti Hasan
Keyword(s):  
Endoplasmic Reticulum ◽  
G Protein Coupled Receptors ◽  
Neuronal Function ◽  
Extracellular Milieu ◽  
Inositol 1,4,5 Trisphosphate ◽  
Membrane Bound ◽  
Trisphosphate Receptor ◽  
Neuronal Physiology ◽  
G Protein Coupled

The IP3R (inositol 1,4,5-trisphosphate receptor) releases Ca2+ from the ER (endoplasmic reticulum) store upon binding to its ligand InsP3, which is thought to be generated by activation of certain membrane-bound G-protein-coupled receptors in Drosophila. Depletion of Ca2+ in the ER store also activates SOCE (store-operated Ca2+ entry) from the extracellular milieu across the plasma membrane, leading to a second rise in cytosolic Ca2+, which is then pumped back into the ER. The role of the IP3R and SOCE in mediating Ca2+ homoeostasis in neurons, their requirement in neuronal function and effect on neuronal physiology and as a consequence behaviour, are reviewed in the present article.

scholarly journals Unraveling the role of polycystin-2/inositol 1,4,5-trisphosphate receptor interaction in Ca2+signaling

2010 ◽  
Vol 3 (6) ◽  
pp. 530-532 ◽  
Author(s):  
Eva Sammels ◽  
Benoit Devogelaere ◽  
Djalila Mekahli ◽  
Geert Bultyncki ◽  
Ludwig Missiaen ◽  
...  
Keyword(s):  
Receptor Interaction ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

scholarly journals Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matias Wagner ◽  
Daniel P. S. Osborn ◽  
Ina Gehweiler ◽  
Maike Nagel ◽  
Ulrike Ulmer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Degradation Pathway ◽  
Therapeutic Interventions ◽  
Spastic Paraplegia ◽  
Ubiquitin E3 Ligase ◽  
Wide Range ◽  
Inositol 1,4,5 Trisphosphate ◽  
Cerebellar Ataxias ◽  
Trisphosphate Receptor

Abstract Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

scholarly journals MNRR1, a Biorganellar Regulator of Mitochondria

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Lawrence I. Grossman ◽  
Neeraja Purandare ◽  
Rooshan Arshad ◽  
Stephanie Gladyck ◽  
Mallika Somayajulu ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Neurodegenerative Diseases ◽  
Family Members ◽  
Unusual Property ◽  
Promoter Element ◽  
Low Oxygen ◽  
Oxidative Stresses ◽  
Graded Response ◽  
Oxygen Tensions

The central role of energy metabolism in cellular activities is becoming widely recognized. However, there are many gaps in our knowledge of the mechanisms by which mitochondria evaluate their status and call upon the nucleus to make adjustments. Recently, a protein family consisting of twin CX9C proteins has been shown to play a role in human pathophysiology. We focus here on two family members, the isoforms CHCHD2 (renamed MNRR1) and CHCHD10. The better studied isoform, MNRR1, has the unusual property of functioning in both the mitochondria and the nucleus and of having a different function in each. In the mitochondria, it functions by binding to cytochromecoxidase (COX), which stimulates respiration. Its binding to COX is promoted by tyrosine-99 phosphorylation, carried out by ABL2 kinase (ARG). In the nucleus, MNRR1 binds to a novel promoter element inCOX4I2and itself, increasing transcription at 4% oxygen. We discuss mutations in both MNRR1 and CHCHD10 found in a number of chronic, mostly neurodegenerative, diseases. Finally, we propose a model of a graded response to hypoxic and oxidative stresses, mediated under different oxygen tensions by CHCHD10, MNRR1, and HIF1, which operate at intermediate and very low oxygen concentrations, respectively.

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