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  • Title: Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death.
    Author: Gutiérrez T, Simmen T.
    Journal: Cell Calcium; 2018 Mar; 70():64-75. PubMed ID: 28619231.
    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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+-flux, ER chaperones and folding assistants guide cellular apoptosis and mitochondrial metabolism.
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