Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization

Boya, Patricia; Cohen, Isabel; Zamzami, Naoufal; Vieira, Helena L.A.; Kroemer, Guido

doi:10.1038/sj.cdd.4401006

Cited by 133 publications

(88 citation statements)

References 26 publications

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“…43 Also, GADD153/ CHOP may sensitize cells to noxious stimuli by inducing the expression of pro-apoptotic genes such as Bax and caspases. 44,45 It is noteworthy that the Bcl-2 protein levels in brainstems of ts1-infected mice are decreased at late stages of disease (data not shown). However, the precise pro-cell-death targets of GADD153/CHOP transcription factor during ts1 infection of the brainstem remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Kim

Waters

Stoica

et al. 2004

Laboratory Investigation

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Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-a. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-a was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca 2 þ ) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca 2 þ homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.

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Section: Discussionmentioning

confidence: 99%

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Kim

Waters

Stoica

et al. 2004

Laboratory Investigation

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“…The increase of ER membrane permeability and calcium release from ER are related with the induction of apoptosis in tumor cells (Boya et al 2002). In comparison to control (pH 7.3), approximately 8-fold enhanced cytosolic Ca 2+ was detected in Raji cells when pH of the growth medium was shifted to 5.8 (Fig.…”

Section: Acidic Environment-induced Apoptosismentioning

confidence: 98%

Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling

Sharma

Kaur

Bhatnagar

et al. 2015

Cell Stress and Chaperones

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The acidic microenvironment around tumor cells is a major determinant in cancer growth, metabolism, and metastasis. However, its role in cancer physiology is still not clearly understood. In the present investigation, an attempt has been made to explore the effect of acidic environment on physiology of cancer cells. Exposure of Raji cells to extracellular acidic environment was associated with enhanced cytosolic calcium level and endoplasmic reticulum stress response. X-box binding protein 1 (XBP1) splicing, CCAAT/ enhancer-binding protein homologous protein (CHOP), and glucose-regulated protein 78 kDa (GRP78) upregulation suggested endoplasmic reticulum stress generation. On the other hand, real-time-based upregulation of Bax gene expression and flow cytometric analysis of cytochrome c release as well as enhanced active caspase-3 further confirmed mitochondrion-mediated events leading to induction of apoptosis. The expression of TP53 and p21 was upregulated. These observations collectively strongly suggest that both endoplasmic reticulum stress-mediated calcium release and Bax targeting might be altering mitochondrion membrane potential which in turn could induce secondary apoptotic signals; subsequently, endoplasmic reticulum stress can also lead to nuclear localization of Nuclear factor-κB (NF-κB) which in turn favors p53 mediated apoptotic signals.

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“…Bax and Bak are also located at the ER membrane (62) where they regulate apoptosis and cause calcium release from the ER through mechanisms that are countered by ER-localized Bcl-2 and Bcl-xL. These signals usually eventually activate the mitochondrial pathway too (63). Apoptosis as a result of mitochondrial permeabilization can also be triggered following lysosomal permeabilization (64) and accumulating evidence indicates that there may be direct linkages between lysosomal functions and both apoptosis and autophagy (65).…”

Section: Regulation Of Apoptosismentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization

Cited by 133 publications

References 26 publications

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling

Apoptosis and autophagy: regulatory connections between two supposedly different processes

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