ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

Abstract

The endoplasmic reticulum (ER) is the primary site for synthesis and folding of secreted and membrane-bound proteins. Proteins are translocated into ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to assist in proper folding. Properly folded proteins traffic from the ER to the Golgi apparatus; misfolded proteins are targeted to degradation. Unfolded protein response (UPR) is a highly regulated intracellular signaling pathway that prevents accumulation of misfolded proteins in the ER lumen. UPR provides an adaptive mechanism by which cells can augment protein folding and processing capacities of the ER. If protein misfolding is not resolved, the UPR triggers apoptotic cascades. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintain cellular homeostasis and determine cell fate under various pathophysiological conditions. Regulated Ca 2þ transfer from the ER to the mitochondria is important in maintaining control of prosurvival/prodeath pathways. We discuss the signaling/communication between the ER and mitochondria and focus on the role of the mitochondrial permeability transition pore in these complex processes.T he ER is an elaborate membranous network present in all eukaryotic cells and responsible for many homeostatic responses that include folding and maturation of newly synthesized secretory and transmembrane proteins (Kleizen and Braakman 2004). In addition, this organelle is also the site of cholesterol and steroid biosynthesis, lipid biosynthesis, assembly of core-asparagine linked oligosaccharides, and membrane and secreted protein biosynthesis. Newly synthesized proteins require proper folding within the ER lumen prior to trafficking to specific destinations in the cell. These cellular processes are initiated when nascent polypeptide chains emerge in ER lumen, where posttranslational modifications such as N-linked glycosylation, and intra-and intermolecular disulfide bond formation facilitate the folding of polypeptides to form specific tertiary and quaternary structures for proper protein function (Molinari 2007). Although the amino acid sequence of the protein determines many

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

“…44 The mitochondrial Ca 2+ overload generated leads to the depolarization of the inner membrane, the release of cytochrome c release and the activation of caspases. 45 In line with the reported occurrence of mitochondrial fission during ER stress [46][47][48] and the role of Drp1 in ER stress-induced apoptosis of pancreatic β-cells, 49 we found that PKA activation led to Drp1 inhibition, as monitored by Drp1 phosphorylation. Moreover, we demonstrated that PKA activation and Drp1 inhibition protected cells from apoptotosis induced by Tu but not by TNF or Eto, thereby identifying a direct mechanistic link for the protective effect of PKA activation in cells undergoing ER stress.…”

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

“…Moreover, knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel endoplasmic reticulum stress-induced death pathway [34]. The endoplasmic reticulum stress is responsible for enhanced cancer cell proliferation and IRE1 knockdown by a dominant-negative construct of IRE1 (dnIRE) resulted in a significant anti-proliferative effect on glioma growth [35,36].…”

“…The activation of endoplasmic reticulum stress is indispensable for tumor growth as it facilitates adaptation to stressful environmental conditions [40]. IRE1 is the most evolutionary conserved sensor that responds to protein misfolding with a highly tuned program aimed to either resolve the stress or direct the cell towards apoptosis in case stress becomes too severe, which makes it a key regulator of cell life and death processes [35,40]. Recently, we have shown that glutamine deprivation affects the expression of proliferation related genes in U87 glioma cells and that IRE1 knockdown modifies glutamine deprivation effects on these genes expression possibly contributing to suppression of glioma cells proliferation [41].…”

Expression of tumor growth related genes in IRE1 knockdown U87 glioma cells: effect of hypoxia

“…T he endoplasmic reticulum stress is an important component of tumor growth, including glioblastoma multiforme, which is a highly aggressive tumor with very poor prognosis, and to date, there is no efficient treatment available [1][2][3]. Diffuse infiltrating gliomas are the most common tumors of the central nervous system.…”