Cytochrome oxidase activity of Fuchs' endothelial dystrophy

Tuberville, Audrey W.; Wood, Thomas O.; McLaughlin, Barbara J.

doi:10.3109/02713688608995175

Cited by 36 publications

(12 citation statements)

References 14 publications

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“…The downregulated transcripts exceeded the upregulated ones and mitochondrial transcripts accounted for the majority of these downregulated genes. These data were consistent with previous studies that showed decreased mitochondrial and pump site densities in FECD41, 77 and indicates a potential decrease in mitochondrial delivery of an adequate energy source. In addition, a comparison between normal and FECD gene libraries revealed a significant decrease in the expression of bicarbonate transporter-related protein-1.…”

Section: Pathophysiologysupporting

confidence: 93%

“…Mitochondrial DNA damage is known to cause dysfunctional mitochondrial protein synthesis, loss of integrity of inner mitochondrial membrane potential, and apoptotic cell death. Interestingly, older studies by Tuberville et al77 showed decreased numbers of mitochondria and a decline in cytochrome oxidase activity in the mitochondria of edematous FECD corneas. The findings of decreased antioxidant defense and oxidative tissue damage in FECD point to an important etiologic component of dystrophic degeneration seen in FECD.…”

Section: Pathophysiologymentioning

confidence: 97%

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Fuchs Endothelial Corneal Dystrophy

2010

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Fuchs endothelial corneal dystrophy (FECD) is characterized by progressive loss of corneal endothelial cells, thickening of Descement’s membrane and deposition of extracellular matrix in the form of guttae. When the number of endothelial cells becomes critically low, the cornea swells and causes loss of vision. The clinical course of FECD usually spans 10–20 years. Corneal transplantation is currently the only modality used to restore vision. Over the last several decades genetic studies have detected several genes, as well as areas of chromosomal loci associated with the disease. Proteomic studies have given rise to several hypotheses regarding the pathogenesis of FECD. This review expands upon the recent findings from proteomic and genetic studies and builds upon recent advances in understanding the causes of this common corneal disorder.

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Section: Pathophysiologysupporting

confidence: 93%

Section: Pathophysiologymentioning

confidence: 97%

Fuchs Endothelial Corneal Dystrophy

2010

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“…[52][53][54] Previous studies have revealed that there are decreased numbers of mitochondria in FECD endothelium, and that activity of cytochrome oxidase, the major respiratory chain enzyme, is decreased in the central area of FECD corneal buttons. 55 Based on our studies, these findings are consistent with oxidative stress-induced mtDNA damage that could lead to loss of integrity of inner mitochondrial membrane potential and apoptotic cell death.…”

Section: Discussionsupporting

confidence: 76%

Evidence of Oxidative Stress in the Pathogenesis of Fuchs Endothelial Corneal Dystrophy

Jurkunas

Bitar

Funaki

et al. 2010

The American Journal of Pathology

263

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Fuchs endothelial corneal dystrophy (FECD) is a progressive, blinding disease characterized by corneal endothelial (CE) cell apoptosis. Corneal transplantation is the only measure currently available to restore vision in these patients. Despite the identification of some genetic factors, the pathophysiology of FECD remains unclear. In this study, we observed a decrease in the antioxidant response element-driven antioxidants in FECD corneal endothelium. We further demonstrated that nuclear factor erythroid 2-related factor 2, a transcription factor known to bind the antioxidant response element and activate antioxidant defense, is down-regulated in FECD endothelium. Importantly, we detected significantly higher levels of oxidative DNA damage and apoptosis in FECD endothelium compared with normal controls and pseudophakic bullous keratopathy (iatrogenic CE cell loss) specimens. A marker of oxidative DNA damage, 8-hydroxy-2-deoxyguanosine, colocalized to mitochondria, indicating that the mitochondrial genome is the specific target of oxidative stress in FECD. Oxidative DNA damage was not detected in pseudophakic bullous keratopathy corneas, whereas it colocalized with terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling-positive cells in FECD samples. Ex vivo, oxidative stress caused characteristic morphological changes and apoptosis of CE, suggestive of findings that characterize FECD in vivo. Together, these data suggest that suboptimal nuclear factor erythroid 2-related factor 2-regulated defenses may account for oxidant-antioxidant imbalance in FECD , which in turn leads to oxidative DNA damage and apoptosis. This study provides evidence that oxidative stress plays a key role in FECD pathogenesis. Corneal endothelium (CE) is a monolayer of cells situated in the anterior chamber surface of the cornea; its primary function is to maintain the cornea in a state of deturgescence through sodium-activated ATPase pumping of water, thus, transparency. Fuchs endothelial corneal dystrophy (FECD) is the most common cause of endogenous corneal endothelial degeneration and is characterized by alterations in corneal endothelial cell morphology, progressive loss of CE cells, and concomitant accumulation of extracellular deposits in the basement membrane that eventually lead to corneal edema and opacity. Because CE does not divide in vivo, loss of endothelial cells seen in FECD is permanent. Corneal transplantation is the only treatment modality that can restore lost vision-rendering FECD the second most common cause of corneal transplants performed on the elderly (Ͼ60 years old) in the United States.2 Lack of knowledge of the mechanism of CE degeneration in FECD precludes the development of pharmacotherapeutics for this common and blinding condition.FECD has been termed a disorder of aging; it is a bilateral and slowly progressive disorder, typically appearing after the age of 60 years. FECD is usually a sporadic condition, but it can be inherited as an autosomal dominant trait.3-5 FECD is characterized by endo...

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“…et al, 2010). Similarly, earlier studies showed decreased numbers of mitochondria in FECD endothelium and a decrease in cytochrome oxidase, the major respiratory chain enzyme, in the central areas of FECD corneal buttons (Johns, D.R., 1995; Tuberville, A.W. et al, 1986).…”

Section: Fuchs Corneal Endothelial Dystrophysupporting

confidence: 69%

Molecular bases of corneal endothelial dystrophies

Schmedt

Silva²,

Ziaei

et al. 2012

Experimental Eye Research

106

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The phrase “corneal endothelial dystrophies” embraces a group of bilateral corneal conditions that are characterized by a non-inflammatory and progressive degradation of corneal endothelium. Corneal endothelial cells exhibit a high pump site density and, along with barrier function, are responsible for maintaining the cornea in its natural state of relative dehydration. Gradual loss of endothelial cells leads to an insufficient water outflow, resulting in corneal edema and loss of vision. Since the pathologic mechanisms remain largely unknown, the only current treatment option is surgical transplantation when vision is severely impaired. In the past decade, important steps have been taken to understand how endothelial degeneration progresses on the molecular level. Studies of affected multigenerational families and sporadic cases identified genes and chromosomal loci, and revealed either Mendelian or complex disorder inheritance patterns. Mutations have been detected in genes that carry important structural, metabolic, cytoprotective, and regulatory functions in corneal endothelium. In addition to genetic predisposition, environmental factors like oxidative stress were found to be involved in the pathogenesis of endotheliopathies. This review summarizes and crosslinks the recent progress on deciphering the molecular bases of corneal endothelial dystrophies.

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Cytochrome oxidase activity of Fuchs' endothelial dystrophy

Cited by 36 publications

References 14 publications

Fuchs Endothelial Corneal Dystrophy

Fuchs Endothelial Corneal Dystrophy

Evidence of Oxidative Stress in the Pathogenesis of Fuchs Endothelial Corneal Dystrophy

Molecular bases of corneal endothelial dystrophies

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