Cited by 104Endoplasmic Reticulum Stress and DiseaseIon Channels and ReceptorsMitochondrial Function and Pathology

Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death

Gutiérrez, Tomas, Simmen, Thomas·2018·Cell Calcium

Abstract

The folding of secretory proteins is a well-understood mechanism, based on decades of research on endoplasmic reticulum (ER) chaperones. These chaperones interact with newly imported polypeptides close to the ER translocon. Classic examples for these proteins include the immunoglobulin binding protein (BiP/GRP78), and the lectins calnexin and calreticulin. Although not considered chaperones per se, the ER oxidoreductases of the protein disulfide isomerase (PDI) family complete the folding job by catalyzing the formation of disulfide bonds through cysteine oxidation. Research from the past decade has demonstrated that ER chaperones are multifunctional proteins. The regulation of ER-mitochondria Ca 2+ crosstalk is one of their additional functions, as shown for calnexin, BiP/GRP78 or the oxidoreductases Ero1α and TMX1. This function depends on interactions of this group of proteins with the ER Ca 2+ handling machinery. This novel function makes perfect sense for two reasons: i. It allows ER chaperones to control mitochondrial apoptosis instantly without a lengthy bypass involving the upregulation of pro-apoptotic transcription factors via the unfolded protein response (UPR); and ii. It allows the ER protein folding machinery to fine-tune ATP import via controlling the speed of mitochondrial oxidative phosphorylation. Therefore, the role of ER chaperones in regulating ER-mitochondria Ca 2+ flux identifies the progression of secretory protein folding as a central regulator of cell survival and death, at least in cell types that secrete large amount of proteins. In other cell types, ER protein folding might serve as a sentinel mechanism that monitors cellular well-being to control cell metabolism and apoptosis. The selenoprotein SEPN1 is a classic example for such a role. Through the control of ER-mitochondria Ca 2+-flux, ER chaperones and folding assistants guide cellular apoptosis and mitochondrial metabolism.

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Crossref · 10.1016/j.ceca.2017.05.015

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Authors
Gutiérrez, T., & Simmen, T.
Affiliations
University of Alberta (CA)
Corresponding author
Simmen, Thomas
Venue
Cell Calcium
Publisher
Elsevier BV
Published
2018-03
Volume
70
Pages
64-75
ISSN
0143-4160 (ISSN-L)
OpenAlex
W2618230221
Cited by
104
References
189
Citations by year
2026: 4 · 2025: 7 · 2024: 14 · 2023: 9 · 2022: 6 · 2021: 16 · 2020: 17 · 2019: 18 · 2018: 12 · 2017: 1
FWCI
1.53
Type
journal article
Language
en
Open access
closed
Locations
  • Cell Calcium (publishedVersion)
  • PubMed (publishedVersion)
Funders
Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-04105)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
endoplasmic reticulum chaperone, mitochondrial calcium, protein folding, BiP/GRP78, calnexin, calreticulin, protein disulfide isomerase, ERO1α, unfolded protein response, apoptosis, mitochondrial metabolism, oxidative phosphorylation, SEPN1
MeSH terms
Endoplasmic Reticulum Chaperone BiP, Animals, Calcium, Endoplasmic Reticulum, Humans, Mitochondria, Cell Death, Molecular Chaperones, Calcium Signaling

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