The integrated stress response as a key pathway downstream of mitochondrial dysfunction

Bilen, Maria; Benhammouda, Sara; Slack, Ruth S.; Germain, Marc

doi:10.1016/j.cophys.2022.100555

Cited by 13 publications

(10 citation statements)

References 114 publications

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“…Under chronic stress, ISR leads to apoptosis. This pathway intersects at the eukaryotic initiation factor subunit eIF2α to slow translation and protein synthesis while allowing adaptive mechanisms to continue [ 18 , 19 ]. Various physiological and pathological changes, including endoplasmic reticulum stress, amino acid deficiency, viral infection, oxidative stress, etc., can activate ISR.…”

Section: Mechanism Of Copper Compound-induced Cell Deathmentioning

confidence: 99%

Potential of Copper and Copper Compounds for Anticancer Applications

Wang

Chen

et al. 2023

Pharmaceuticals

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Inducing cancer cell death has always been a research hotspot in life sciences. With the continuous deepening and diversification of related research, the potential value of metal elements in inducing cell death has been explored. Taking iron as an example, ferroptosis, mainly characterized by increasing iron load and driving the production of large amounts of lipid peroxides and eventually leading to cell death, has recently attracted great interest in the cancer research community. After iron, copper, a trace element, has received extensive attention in cell death, especially in inducing tumor cell death. Copper and its complexes can induce autophagy or apoptosis in tumor cells through a variety of different mechanisms of action (activation of stress pathways, arrest of cell cycle, inhibition of angiogenesis, cuproptosis, and paraptosis), which are promising in cancer therapy and have become new hotspots in cancer treatment research. This article reviews the main mechanisms and potential applications of novel copper and copper compound-induced cell death, focusing on copper compounds and their anticancer applications.

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Section: Mechanism Of Copper Compound-induced Cell Deathmentioning

confidence: 99%

Potential of Copper and Copper Compounds for Anticancer Applications

Wang

Chen

et al. 2023

Pharmaceuticals

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“…Sodium–potassium pumping enzymes and some protein synthesis pathways are regulated by protein posttranslational modifiers including being inhibited by redox sensitive S-glutathionylation [ 50 , 219 ]. Thermal and oxidative distress in mitochondria can cause their dysfunction invoking a cellular integrated stress response, modifying the nuclear transcriptome and slowing down protein synthesis in the cytoplasm [ 220 ]. The depletion of GSH or an increase in GSSG may also lead to some protein S-glutathionylation inhibition of protein synthesis [ 221 ].…”

Section: Sleep Theoriesmentioning

confidence: 99%

Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles

Richardson

Mailloux

2023

Antioxidants

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Although circadian biorhythms of mitochondria and cells are highly conserved and crucial for the well-being of complex animals, there is a paucity of studies on the reciprocal interactions between oxidative stress, redox modifications, metabolism, thermoregulation, and other major oscillatory physiological processes. To address this limitation, we hypothesize that circadian/ultradian interaction of the redoxome, bioenergetics, and temperature signaling strongly determine the differential activities of the sleep–wake cycling of mammalians and birds. Posttranslational modifications of proteins by reversible cysteine oxoforms, S-glutathionylation and S-nitrosylation are shown to play a major role in regulating mitochondrial reactive oxygen species production, protein activity, respiration, and metabolomics. Nuclear DNA repair and cellular protein synthesis are maximized during the wake phase, whereas the redoxome is restored and mitochondrial remodeling is maximized during sleep. Hence, our analysis reveals that wakefulness is more protective and restorative to the nucleus (nucleorestorative), whereas sleep is more protective and restorative to mitochondria (mitorestorative). The “redox–bioenergetics–temperature and differential mitochondrial–nuclear regulatory hypothesis” adds to the understanding of mitochondrial respiratory uncoupling, substrate cycling control and hibernation. Similarly, this hypothesis explains how the oscillatory redox–bioenergetics–temperature–regulated sleep–wake states, when perturbed by mitochondrial interactome disturbances, influence the pathogenesis of aging, cancer, spaceflight health effects, sudden infant death syndrome, and diseases of the metabolism and nervous system.

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“…The integrated stress response (ISR) describes the complex network of signalling pathways activated by eukaryotic cells in response to stress. [418][419][420] A key feature of the ISR is the downregulation of global protein synthesis by the inhibition of translation. [418][419][420] All three acute treatments downregulated both mRNA splicing and ribosome biogenesis proteins, consistent with a decrease in global protein production.…”

Section: The Responses Of Ln18 Gbm Cells To Treatmentmentioning

confidence: 99%

“…[418][419][420] A key feature of the ISR is the downregulation of global protein synthesis by the inhibition of translation. [418][419][420] All three acute treatments downregulated both mRNA splicing and ribosome biogenesis proteins, consistent with a decrease in global protein production. As has previously been observed, the downregulation of ribosome biogenesis proteins was particularly striking in response to doxorubicin.…”

Section: The Responses Of Ln18 Gbm Cells To Treatmentmentioning

confidence: 99%

“…132,423 Furthermore, mitochondrial dysfunction and ER stress are two conditions that initiate the ISR. 419 Crosstalk between these two organelles is important in the regulation of reactive oxygen species (ROS) such as those produced by IR, so it is not surprising that the acute treatments, particularly IR, upregulated proteins involved in trafficking across mitochondrial and ER membranes. 420 Additionally, there is a complex interplay between nuclear and mitochondrial activity in DNA damage responses such as DNA repair, cell cycle checkpoints and apoptosis.…”

Section: The Responses Of Ln18 Gbm Cells To Treatmentmentioning

confidence: 99%

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BCL6 is a context-dependent mediator of the glioblastoma therapy response

Tribe¹

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<p>Glioblastoma is a rapidly fatal brain cancer with no cure. The resistance of glioblastoma tumours to available therapies means that more effective treatments are desperately needed. Previous research showed that the transcriptional repressor protein BCL6 is upregulated by chemo- and radiotherapy in glioblastoma and that inhibition of BCL6 enhances the effectiveness of these therapies. Therefore, BCL6 is a promising target to improve the efficacy of available treatments for glioblastoma. BCL6 is known as a transcriptional repressor in germinal centre B cells and an oncogene in lymphoma, as well as in other cancers. However, previous research indicated that BCL6 induced by therapy in glioblastoma may not act as a transcriptional repressor. This thesis aimed to clarify the role of BCL6 in the therapy response of glioblastoma. The effect of BCL6 inhibition on the whole proteome response of glioblastoma cells to DNA-damaging treatments was investigated. This confirmed that BCL6 was involved in the therapy response of glioblastoma and that acute irradiation appeared to cause BCL6 to switch from a repressor of the DNA damage response to a promoter of stress response signalling. Rapid immunoprecipitation mass spectrometry of endogenous proteins enabled identification of proteins associated with BCL6 in untreated and irradiated glioblastoma cells. BCL6 appeared to be a transcriptional regulator in untreated glioblastoma and its association with the corepressor NCOR2 was validated using proximity ligation assays. However, association with nuclear proteins was lost in response to acute irradiation. This was accompanied by the irradiation-induced association of BCL6 with plasma membrane proteins. Targeted long-read transcript sequencing did not reveal differential alternative splicing of BCL6 in response to acute irradiation. This indicated that the canonical BCL6 protein was expressed in irradiated glioblastoma cells and that the change in BCL6 function must be mediated by mechanisms other than the production of splice variants, such as through post-translational modification. Overall, these results support the hypothesis that BCL6 is involved in the therapy resistance of glioblastoma cells but reveal that its activity is context-dependent and may be mediated by the intensity of cellular stress.</p>

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The integrated stress response as a key pathway downstream of mitochondrial dysfunction

Cited by 13 publications

References 114 publications

Potential of Copper and Copper Compounds for Anticancer Applications

Potential of Copper and Copper Compounds for Anticancer Applications

Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles

BCL6 is a context-dependent mediator of the glioblastoma therapy response

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