Stress-responsive regulation of mitochondria through the ER unfolded protein response

Rainbolt, T. Kelly; Saunders, Jaclyn M.; Wiseman, R. Luke

doi:10.1016/j.tem.2014.06.007

Cited by 167 publications

(156 citation statements)

References 97 publications

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“…9,10,12 Following an impairment of homeostasis, the UPR serves as an apoptosis executor. This phenomenon has been accepted as indicating that the function of UPR-mediated apoptosis is to protect the organism from damaged cells that cannot ascertain the normal signaling components.…”

Section: Discussionmentioning

confidence: 99%

“…9 The ''life or death'' decision by the UPR serves as a universal underlying mechanism in the pathogenesis of various diseases, including neurodegenerative diseases, inflammation, metabolic disorders, liver dysfunction, and cancer. 9,10,13 For instance, accumulating evidence now supports a linkage of protein misfolding and inclusion body formation with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. [23][24][25][26] In the field of eye disease, misfolded proteins and subsequent UPR signaling are related to pathogenesis in certain types of retinitis pigmentosa and Stargart-like macular degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…8 A wide range of stresses, including increased secretory protein production, glucose deprivation, and hypoxia, induces the accumulation of unfolded or misfolded proteins in the ER lumen. 9,10 The conditions within the ER are monitored by the UPR signaling pathway, and activation of the UPR restores protein folding homeostasis by reducing protein translation, increasing ER chaperone expression, and degrading misfolded proteins. [9][10][11] However, prolonged ER stress impairs protein homeostasis, which then triggers the UPR to induce apoptosis.…”

mentioning

confidence: 99%

“…9,10 The conditions within the ER are monitored by the UPR signaling pathway, and activation of the UPR restores protein folding homeostasis by reducing protein translation, increasing ER chaperone expression, and degrading misfolded proteins. [9][10][11] However, prolonged ER stress impairs protein homeostasis, which then triggers the UPR to induce apoptosis. 9,10,12 Consequently, targeting the UPR has emerged as a promising therapeutic modality for the treatment of diseases related to accumulation of unfolded or misfolded proteins in the ER.…”

mentioning

confidence: 99%

“…[9][10][11] However, prolonged ER stress impairs protein homeostasis, which then triggers the UPR to induce apoptosis. 9,10,12 Consequently, targeting the UPR has emerged as a promising therapeutic modality for the treatment of diseases related to accumulation of unfolded or misfolded proteins in the ER. [13][14][15] Our aim in the present study was to investigate the potential involvement of the UPR in FECD as a possible contributor to the underlying pathophysiological mechanism.…”

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confidence: 99%

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Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy

Okumura

Kitahara

Okuda

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Okumura N, Kitahara M, Okuda H, et al. Sustained activation of the unfolded protein response induces cell death in Fuchs' endothelial corneal dystrophy. Invest Ophthalmol Vis Sci. 2017;58:3697-3707. DOI: 10.1167/iovs.16-21023 PURPOSE. The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death. METHODS.Descemet's membranes with corneal endothelial cells (CECs) were obtained during keratoplasty, and expression of aggresomes, type 1 collagen, fibronectin, and agrin was evaluated. Endoplasmic reticulum (ER) stress of immortalized human CECs from non-FECD subjects and from FECD patients (iHCEC and iFECD, respectively) were evaluated. The effect of MG132-mediated aggresome formation on the UPR and intrinsic pathway and the effect of mitochondrial damage on UPR were also examined. The effect of CHOP knockdown on the ER stress-mediated intrinsic pathway was also evaluated.RESULTS. Aggresome formation was higher in iFECD than in iHCEC and was colocalized with type 1 collagen, fibronectin, and agrin. GRP78, phosphorylated IRE1, PERK, and CHOP showed higher activation in iFECD than in iHCEC. MG132-mediated aggresome formation upregulated ER stress sensors, the mitochondrial membrane potential drop, cytochrome c release to the cytoplasm, and activation of caspase-9 and -3. By contrast, staurosporinemediated mitochondrial damage did not induce ER stress. Knockdown of CHOP attenuated the ER stress-induced cleavage of caspase-9, which is caused by intrinsic pathway activation.CONCLUSIONS. Excessive synthesis of extracellular matrix proteins induced unfolded protein accumulation in FECD. Prolonged ER stress-mediated cell death, occurring via the intrinsic apoptotic signaling pathway, therefore might be associated with the pathogenesis of FECD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy

Okumura

Kitahara

Okuda

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Cardiotoxicity of Drugs

Varga

Pacher

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective

Majumder

Singh

George

et al. 2018

J of Cellular Biochemistry

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Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body’s vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy’s effects on the vascular system. An ancient Indian form of exercise called ‘yoga’ causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia‐reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti‐pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti‐inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow–derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior’s role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.

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Stress-responsive regulation of mitochondria through the ER unfolded protein response

Cited by 167 publications

References 97 publications

Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy

Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy

Cardiotoxicity of Drugs

Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective

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