Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy

Kumar, Varun; Jurkūnas, Ūla V.

doi:10.3390/cells10081888

Cited by 32 publications

(24 citation statements)

References 51 publications

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“…Unlike ultraviolet B (UVB) light that causes DNA damage directly, UVA light causes macromolecular damage indirectly via the production of ROS that results from irradiation (14). DNA damage and apoptotic cell death in particular have been the focus of studies examining UV mediated cell death in FECD (9,(15)(16)(17). However, UVA is also known to result in lipid peroxidation and nonapoptotic oxidative cell death (18,19).…”

Section: Introductionmentioning

confidence: 99%

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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Fuchs endothelial corneal dystrophy (FECD), a progressive polygenic disease that causes degeneration of the corneal endothelium, is the leading indication for corneal transplantation in the U.S. Characteristically, loss of corneal endothelial cells and formation of degenerative extracellular guttae result in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor. FECD pathogenesis is linked to oxidative stress and environmental exposure to ultraviolet A (UVA), and impaired endogenous response to oxidative stress is common to the disease across multiple genotypes. UV irradiation is also known to cause cellular damage by ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation. Although a possible role for ferroptosis in FECD has been postulated to account for the increased susceptibility to oxidative damage and lipid peroxidation, this has not been explored systematically. In this study, we investigated the roles of genetic background and UVA exposure in causing lipid membrane damage and endothelial cell degeneration in FECD. We first sought clinical evidence of iron-mediated lipid peroxidation in surgical samples obtained from FECD patients undergoing endothelial keratoplasty, and found increased levels of cytosolic ferrous iron (Fe2+) and evidence of lipid peroxidation were present in end-stage diseased tissues compared with healthy human donor corneas. Next, using immortalized (F35T) and primary cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found that alterations in gene and protein expression involved in ferroptosis were conserved in both cell culture and tissue models of FECD disease compared to controls, including elevated levels of the ferroptosis-specific marker transferrin receptor 1. F35T immortalized cells showed significantly higher basal lipid peroxidation than control HCEC-B4G12 cells, indicating higher susceptibility to ferroptosis attributable to genetic background. Then, we tested the impact of physiologically relevant doses of UVA irradiation on F35T cell cultures and found increased cytosolic Fe2+ iron levels indicating a role for ferroptosis in FECD disease progression. Finally, we tested the effects of inhibitory ferroptosis molecules. We found that F35T cells were more prone to RSL3 induced ferroptosis than healthy controls with deferoxamine chelation which indicated increased susceptibility in FECD cells, and cell death could be prevented after experimentally-induced ferroptosis using solubilized antioxidant ubiquinol indicating a role for anti-ferroptosis therapies. This investigation demonstrates that FECD genetic background and UVA exposure contribute to basal and incidental iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated oxidative damage and disease progression in FECD.

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Section: Introductionmentioning

confidence: 99%

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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“…Oxidative stress also plays a major role in the chronic degenerative process of HCE in FECD. [43][44][45] The oxidative cellular stress that caused hCEC degeneration was accompanied by reduced miR-34a expression 1 (Fig. 6) and dysfunctional mitochondria biogenesis 1 as well as the increased release of miR-184 and -24-J o u r n a l P r e -p r o o f 21 3p (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cellular Interplay Through Extracellular Vesicle miR-184 Alleviates Corneal Endothelium Degeneration

Yamashita¹,

Asada²,

Ueno³

et al. 2022

Ophthalmology Science

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“…However, reduced basal autophagy level is indirect cause of endothelial dysfunction and cell death. Majorly, mitophagy is impaired during endothelial cell dysfunction which is responsible for oxidative stress alleviating and recycling impaired mitochondria [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell autophagy in the context of disease development

Marzoog

2022

Anat Cell Biol

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Endothelial cells (EC) are the anatomical boundaries between the intravascular and extravascular space. Damage to ECs is catastrophic and induces endothelial cell dysfunction. The pathogenesis is multifactorial and involves dysregulation in the signaling pathways, membrane lipids ratio disturbance, cell-cell adhesion disturbance, unfolded protein response, lysosomal and mitochondrial stress, autophagy dysregulation, and oxidative stress. Autophagy is a lysosomal-dependent turnover of intracellular components. Autophagy was recognized early in the pathogenesis of endothelial dysfunction. Autophagy is a remarkable patho (physiological) process in the cell homeostasis regulation including EC. Regulation of autophagy rate is disease-dependent and impaired with aging. Up-regulation of autophagy induces endothelial cell regeneration/differentiation and improves the function of impaired ones. The paper scrutinizes the molecular mechanisms and triggers of EC dysregulation and current perspectives for future therapeutic strategies by autophagy targeting.

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Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy

Cited by 32 publications

References 51 publications

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Cellular Interplay Through Extracellular Vesicle miR-184 Alleviates Corneal Endothelium Degeneration

Endothelial cell autophagy in the context of disease development

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