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

Okumura, Naoki; Kitahara, Miu; Okuda, Hiroyuki; Hashimoto, Keisuke; Ueda, Emi; Nakahara, Makiko; Kinoshita, Shigeru; Young, Robert D.; Quantock, Andrew J.; Tourtas, Theofilos; Schlötzer‐Schrehardt, Ursula; Kruse, Friedrich E.; Koizumi, Noriko

doi:10.1167/iovs.16-21023

Cited by 36 publications

(34 citation statements)

References 38 publications

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“…In addition, treatment options for preserving the release of functional ER calcium suppress cytokine-mediated beta cell death in diabetes 36 . Recently, ER stress was discovered to trigger the apoptosis of corneal endothelial cells through the intrinsic signaling pathway 37 , 38 . Thus, we postulated that the chronic elevation of aqueous cytokine levels may initiate the apoptosis of corneal endothelial cells via oxidative or ER stress.…”

Section: Discussionmentioning

confidence: 99%

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor

Yagi-Yaguchi

Yamaguchi

Higa

et al. 2017

Sci Rep

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Annual reduction rate of corneal endothelial cell density (ECD) varies among etiologies, however, the cause of chronic endothelial cell loss is still unknown. We recently reported the elevation of inflammatory cytokines in the aqueous humor (AqH) in eyes with bullous keratopathy and low ECD. To evaluate the association between ECD and aqueous cytokine levels, we collected a total of 157 AqH samples prospectively. The AqH levels of cytokines were measured and multivariate analyses were conducted to find the correlation between ECD, aqueous cytokine levels and clinical factors, such as number of previous intraocular surgeries and protein concentration in AqH. As a result, ECD was negatively correlated with specific cytokine levels, including IL-1α, IL-4, IL-13, MIP-1β, TNF-α and E-selectin (all P < 0.05). The aqueous cytokine levels showed different correlations with these clinical factors; the number of previous intraocular surgeries was associated with all cytokines except MIP-1α. The AqH protein concentration and the status of intraocular lens showed similar patterns of elevation of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, MIP-1β, MCP-1, E-selectin, P-selectin and sICAM-1. In conclusion, elevation of AqH cytokine levels was associated with reduced ECDs. AqH cytokine levels showed significant correlations with clinical factors associated with low ECDs.

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Section: Discussionmentioning

confidence: 99%

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor

Yagi-Yaguchi

Yamaguchi

Higa

et al. 2017

Sci Rep

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“…The same research group subsequently showed that homozygous knock-in of Col8a2 Q455K/Q455K , a causal gene for early-onset FECD, was sufficient to induce FECD-like ocular features in mice, and these changes were linked with UPR-associated apoptosis [ 40 ]. Recently, our group showed that ECM components, such as type I collagen and fibronectin, form aggregates of unfolded proteins in the corneal endothelium of FECD patients [ 41 ]. We also showed that activation of transforming growth factor-β (TGF-β) signaling causes a chronic overload of ECM proteins within the ER, which induces an accumulation of unfolded protein and activation of the intrinsic apoptotic pathway through the UPR [ 42 ].…”

Section: Pathophisiologymentioning

confidence: 99%

“…Accumulating evidence suggests that oxidative stress, induced by mitochondrial dysfunction, damages corneal endothelial cells. Interestingly, ER stress activates the intrinsic apoptotic pathway (the mitochondrial pathway) in the corneal endothelium, as it does in other cell types [ 41 ]. Future studies will likely elucidate the nature of the involvement of both ER stress and oxidative stress in the pathogenesis of FECD.…”

Section: Pathophisiologymentioning

confidence: 99%

Perspective of Future Potent Therapies for Fuchs Endothelial Corneal Dystrophy

Okumura¹,

Koizumi²

2018

TOOPHTJ

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Background:Fuchs Endothelial Corneal Dystrophy (FECD) is a progressive disease that affects the corneal endothelium in both eyes. Recent studies have identified a novel genetic basis for FECD, and basic research findings have provided evidence for its underlying pathophysiology. Since its first description by Ernst Fuchs in 1910, the only therapeutic choice has been corneal transplantation using donor corneas. However, accumulating evidence suggests that a change in this “rule” may be imminent.Conclusions:This article reviews the current knowledge of the genetics and pathophysiology of FECD, and it introduces some potent therapeutic modalities that show promise as new treatments for this disorder.

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“…The redox state within the cell affects ER protein folding machinery, and can result in Unfolded Protein Response (UPR) 41 , a cascade of signaling events that arise during ER stress. Studies in FCED have detected ER stress and UPR 22 . Here, we show that mitochondrial ROS, which could alter redox levels in ER, can also induce ER stress in the Slc4a11 KO model of CHED.…”

Section: Discussionmentioning

confidence: 99%

“…21 . Previous work has identified ER dysfunction in FCED 22 , and we further investigated whether mitoROS in Slc4a11 KO MCEC can affect ER stress.…”

Section: Er Stress and Unfolded Protein Response Is Activated In Slc4mentioning

confidence: 99%

MitoROS due to loss ofSlc4a11in corneal endothelial cells induces ER stress, lysosomal dysfunction and impairs autophagy

Shyam

Ogando

Choi

et al. 2020

Preprint

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Recent studies from Slc4a11 KO mice have identified mitochondrial dysfunction as a major contributor toward oxidative stress and cell death in Congenital Hereditary Endothelial Dystrophy. Here we asked if this stress activated autophagy in the Slc4a11 KO cell line and in KO mouse endothelial tissue. Early indicators of autophagy, phospho-mTOR and LC3-II indicated activation, however P62 was elevated suggesting an impairment of autophagy flux. The activity and the number of lysosomes, the organelle responsible for the final degradation of autophagy substrates, were found to be reduced in the KO. In addition, the expression of the master regulator of lysosomal function and biogenesis, TFEB, was significantly reduced in the KO corneal endothelia. Also, we observed increased Unfolded Protein Response, as well as elevated expression of ER stress markers, BIP and CHOP. To test if lysosomal and ER stress stems from elevated mitochondrial ROS, we treated Slc4a11 KO corneal endothelial cells with the mitochondrial ROS quencher, MitoQ. MitoQ restored lysosomal enzymes as well as TFEB, reduced ER stress, and increased autophagy flux. MitoQ injections of Slc4a11 KO mice decreased corneal edema, the major phenotype associated with CHED. We conclude that mitochondrial ROS causes ER stress and lysosomal dysfunction with impairment of autophagy in Slc4a11 KO corneal endothelium. Our study is the first to identify the presence as well as cause of lysosomal dysfunction and ER stress in an animal model of CHED, and to characterize inter-organelle relationship in a corneal cell type.

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

Cited by 36 publications

References 38 publications

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor

Perspective of Future Potent Therapies for Fuchs Endothelial Corneal Dystrophy

MitoROS due to loss ofSlc4a11in corneal endothelial cells induces ER stress, lysosomal dysfunction and impairs autophagy

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