JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death

Win, Sanda; Than, Tinaung; Fernández-Checa, José C.; Kaplowitz, Neil

doi:10.1038/cddis.2013.522

Cited by 148 publications

(185 citation statements)

References 42 publications

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“…It is possible that mitochondrial dysfunction can induce ER stress [37,39] and vice versa [24,40,41] . To explore this, we first used mitochondria-targeted enhanced yellow fluorescent protein (Mito-EYFP) to monitor the morphological changes of mitochondria during Res-006 treatment in HepG2 cells ( Figure 3A).…”

Section: Res-006 Dysregulates Mitochondrial Dynamics and Disrupts Mmpmentioning

confidence: 99%

The novel resveratrol derivative 3,5-diethoxy-3′,4′-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro

et al. 2017

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Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a well-known polyphenol that is present in grapes, peanuts, pine seeds, and several other plants. Resveratrol exerts deleterious effects on various types of human cancer cells. Here, we analyzed the cell death-inducing mechanisms of resveratrol-006 (Res-006), a novel resveratrol derivative in human liver cancer cells in vitro. Res-006 suppressed the viability of HepG2 human hepatoma cells more effectively than resveratrol (the IC 50 values were 67.2 and 354.8 μmol/L, respectively). Co-treatment with the ER stress regulator 4-phenylbutyrate (0.5 mmol/L) or the ROS inhibitor N-acetyl-L-cysteine (NAC, 1 mmol/L) significantly attenuated Res-006-induced HepG2 cell death, suggesting that pro-apoptotic ER stress and/or ROS may govern the Res-006-induced HepG2 cell death. We further revealed that treatment of HepG2 cells with Res-006 (65 μmol/L) immediately elicited the dysregulation of mitochondrial dynamics and the accumulation of mitochondrial ROS. It also collapsed the mitochondrial membrane potential and further induced ER stress and cell death. These events, except for the change in mitochondrial morphology, were prevented by the exposure of the HepG2 cells to the mitochondrial ROS scavenger, Mito-TEMPO (300-1000 μmol/L). The results suggest that Res-006 may kill HepG2 cells through cell death pathways, including the ER stress initiated by mitochondrial ROS accumulation. The cell death induced by this novel resveratrol derivative involves crosstalk between the mitochondria and ER stress mechanisms.

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Section: Res-006 Dysregulates Mitochondrial Dynamics and Disrupts Mmpmentioning

confidence: 99%

The novel resveratrol derivative 3,5-diethoxy-3′,4′-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro

et al. 2017

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“…Redox disturbances, as evidenced by an increase in ROS, are an essential component in many of these pathways. The following amplification loops are highlighted: (1, red) ER-stress-induced Ca 2+ flux across the mitochondria-associated ER membrane (MAM) stimulates MOMP and respiratory chain (RC) dysfunction, leading to ROS increase, which positively feeds back on Ca 2+ release channels or causes further ER stress (Raturi et al, 2014); (2, blue) an increase of cytosolic Ca 2+ in response to ER stress triggers the CaMKII-JNK-NOX2/NOX4-PKR-CHOP pathway to amplify ER Ca 2+ release through transcriptional induction of Ero1a (Li et al, 2010a;Pedruzzi et al, 2004); (3, green) activated FIS1 forms a complex with BAP31 (and possibly the ER-stress-inducible CDIP1), which activates caspase-8 (CASP8) to amplify pro-apoptotic Ca 2+ and BCL2 input on mitochondria (Iwasawa et al, 2011;Namba et al, 2013); (4, violet) activation of ASK1, and thus JNK, downstream of ER stress is amplified by formation of a JNK-Sab complex (Sab is also known as SH3BP5), RC dysfunction and ROS-dependent activation of ASK1 (Win et al, 2014). For references and details on the pathways marked by black arrows refer to the main text.…”

Section: The Er-stress-mitochondrial Signaling Axismentioning

confidence: 99%

“…In addition, ASK1 is activated by ER stress through IRE1 (Urano et al, 2000). Sustained activation of ASK1, and thus JNK, following ER stress crucially depends on JNK-dependent inhibition of mitochondrial respiration and resulting ROS production (Win et al, 2014) (Fig. 3).…”

Section: Crosstalk To Map Kinases and Antioxidant Pathwaysmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

154

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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“…1: II-1, II-2, II-2-4). (2) Activated JNK interacts with Sab, a mitochondrial JNK binding protein, and consequently impairs respiration, which increases mitochondrial reactive oxygen species (ROS) culminating in apoptosis (Win et al, 2014) (Fig. 1: II-2-1).…”

Section: Other Signal Pathways Related To Ire1α and Ire1βmentioning

confidence: 99%

“…The formation of disulfide in the ER is believed to contribute to 25% of the ROS generated by the cell (Chaudhari et al, 2014). Furthermore, mitochondrial ROS are increased by JNK/Sab complex activation when ER stress activates the JNK (Win et al, 2014). CHOP induces endoplasmic reticulum oxidoreductase 1α (ERO1α), which hyperoxidizes the ER environment and further commits the cell to apoptosis .…”

Section: Er Stress and Apoptosismentioning

confidence: 99%

Molecular signal networks and regulating mechanisms of the unfolded protein response

Gong

Wang

et al. 2017

J. Zhejiang Univ. Sci. B

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Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1α (IRE1α)). Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-phospholipase C-γ (PLCγ)-mammalian target of rapamycin complex 1 (mTORC1) pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IRE1α also can be activated by activated RAC-alpha serine/threonine-protein kinase (AKT). A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species (ROS), Ca 2+ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and P38, when cellular damage exceeds the capacity of this adaptive response.

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JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death

Cited by 148 publications

References 42 publications

The novel resveratrol derivative 3,5-diethoxy-3′,4′-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro

The novel resveratrol derivative 3,5-diethoxy-3′,4′-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro

Redox controls UPR to control redox

Molecular signal networks and regulating mechanisms of the unfolded protein response

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