An Involvement of Oxidative Stress in Endoplasmic Reticulum Stress and Its Associated Diseases

Bhandary, Bidur; Marahatta, Anu; Kim, Hyung‐Ryong; Chae, Han-Jung

doi:10.3390/ijms14010434

Cited by 339 publications

(265 citation statements)

References 126 publications

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“…4D) (28). ER stress can promote mitochondrial damage (29), and autophagy/ mitophagy is responsible for removal and recycling of damaged or aged mitochondria (30). Congruently, EM analysis revealed accumulation of fused, electron-dense, and abnormally looking mitochondria, containing fewer and swollen cristae in Atg7 Δpan pancreata (Fig.…”

Section: Loss Of Atg7 Results In Er Stress and Mitochondrial Dysfunctmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

203

182

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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Section: Loss Of Atg7 Results In Er Stress and Mitochondrial Dysfunctmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

203

182

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“…Enzymatic mechanisms are numerous and include NADPH oxidases, nitric oxide synthases, xanthine oxidase, cytochrome P450 enzymes, cyclooxygenases, and lipoxygenases (Gorrini et al 2013b). The endoplasmic reticulum also serves as a source of ROS during protein folding via protein disulfide isomerase, endoplasmic reticulum oxidoreductin, NADPH oxidase (especially NOX4), and other mechanisms (Malhotra et al 2008;Bhandary et al 2012;Higa and Chevet 2012). Peroxisomes produce ROS through b-oxidation of fatty acids and flavin oxidase activity (Schrader and Fahimi 2006).…”

Section: Sources and Effects Of Rosmentioning

confidence: 99%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

229

164

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Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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“…This H 2 O 2 is required for the re-oxidation of the reduced PDI protein by ER-localised glutathione peroxidases (GPx7 and GPx8) and potentially also by peroxiredoxin 4 (Prdx4). On the other hand, the activation of the ER stress pathway, which may lead to apoptotic cell death, has also been associated to the fulminant ROS generation in the ER (Malhotra et al 2008, Bhandary et al 2012, Cao & Kaufman 2014.…”

Section: Introductionmentioning

confidence: 99%

Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Lortz

Lenzen

Mehmeti

2015

Journal of Molecular Endocrinology

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Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H 2 O 2 ). Because of the high rate of insulin biosynthesis and the low expression of H 2 O 2 -inactivating enzymes in pancreatic b cells, it has been proposed that the luminal H 2 O 2 concentration might be very high. As the role of this H 2 O 2 in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H 2 O 2 removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H 2 O 2 significantly with a threefold increase of the EC 50 value for H 2 O 2 . However, the expression of cytokine-induced ER stress genes and viability after incubation with b cell toxic cytokines (IL1b alone or together with TNFaCIFNg) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H 2 O 2 reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H 2 O 2 toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H 2 O 2 in the ER in spite of a reduced insulin transcription and processing.

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An Involvement of Oxidative Stress in Endoplasmic Reticulum Stress and Its Associated Diseases

Cited by 339 publications

References 126 publications

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Cancer, Oxidative Stress, and Metastasis

Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

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