Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily E.; Chen, Yuming; Santos, Janine H.; Jurkunas, Ula V.

doi:10.1089/ars.2015.6532

Cited by 68 publications

(84 citation statements)

References 45 publications

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“…Mitochondria are the main source of cellular energy metabolism. Mitochondrial mass is decreased in the Fuchs endothelial corneal dystrophy, and the corneal endothelial cells subjected to oxidative stress (Halilovic et al, 2016). The abundance of mitochondria in the corneal endothelial cells is essential for maintaining corneal hydration and transparency.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects Oncorneal Endothelium During Intracameral Irrigation Using N-(2)-l-alanyl-l-Glutamine

Jin

Wang

et al. 2020

Front. Pharmacol.

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Corneal endothelial disease is a global sight-threatening disease, and corneal transplantation using donor corneas remains the sole therapeutic option. A previous work demonstrated that N (2)-alanyl-glutamine (Ala-Gln) protected against apoptosis and cellular stress, and maintained intestinal tissue integrity. In this pursuit, the present study aimed to examine the effect of Ala-Gln in the protection of the corneal endothelium and expand its range of potential clinical applications. Mice in the control group were intracamerally irrigated with Ringers lactate injection, whereas those in the experimental group were irrigated with Ringers lactate injection containing Ala-Gln. The mean intraocular pressure increased to 44 ± 3.5 mm Hg during intracameral irrigation (normal range 10.2 ± 0.4 mmHg). In vivo confocal microscopy results showed that the addition of Ala-Gln protected the morphology, structure, and density of the corneal endothelial cells. Optical Coherence Tomography (OCT) measurements showed that corneal thickness was not significantly different between the two groups, because of the immediate corneal edema after irrigation, but the addition of Ala-Gln obviously promoted the recovery of the corneal edema. Scanning electron microscopy indicated that the corneal endothelial cells were severely ruptured and exfoliated in the Ringer's group accompanied with cellular edema, when compared with the Ala-Gln group. The intracameral irrigation using Ala-Gln protected the structure and expression of cytoskeleton and Na-K-ATPase, which exhibited a regular distribution and significantly increased expression in comparison to Ringer's group. Furthermore, Ala-Gln maintained the mitochondrial morphology and increased the activity of mitochondria. Moreover, transmission electron microscopy showed that intracameral irrigation of Ala-Gln reversed the ultrastructural changes induced by the acute ocular hypertension in mice. Our study demonstrates that the intracameral irrigation of Ala-Gln effectively maintained the corneal endothelial pump function and barrier function by protecting the mitochondrial function and preventing the rearrangement of cytoskeleton in acute ocular hypertension in mice.

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Section: Discussionmentioning

confidence: 99%

Protective Effects Oncorneal Endothelium During Intracameral Irrigation Using N-(2)-l-alanyl-l-Glutamine

Jin

Wang

et al. 2020

Front. Pharmacol.

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“…treatment leads to rosette formation, mitochondrial dysfunction and activation of apoptosis in FECD cells 13 . Moreover, subsequent work by the same group showed that the loss of mitochondria in FECD would be caused by the activation of mitophagy 14 .…”

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confidence: 97%

Chronology of cellular events related to mitochondrial burnout leading to cell death in Fuchs endothelial corneal dystrophy

Méthot

Proulx

Brunette

et al. 2020

Sci Rep

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fuchs endothelial corneal dystrophy (fecD) is a degenerative eye disease characterized by corneal endothelial cell (CEC) death and the formation of guttae, an abnormal thickening of CEC's basement membrane. At the tissue level, an oxidative stress causing mitochondrial damage and CEC death have been described to explain FECD pathogenesis. At the cellular level, our group has previously observed significant variability in the mitochondrial mass of FECD CECs. This led us to hypothesize that mitochondrial mass variability might play a key role in the chronology of events eventually leading to CEC death in FECD. We thus used different fluorescent markers to assess mitochondrial health and functionality as a function of mitochondrial mass in FECD corneal endothelial explants, namely, intramitochondrial calcium, mitochondrial membrane potential, oxidation level and apoptosis. This has led us to describe for the first time a sequence of events leading to what we referred to as a mitochondrial burnout, and which goes as follow. FECD CECs initially compensate for endothelial cell losses by incorporating mitochondrial calcium to help generating more ATP, but this leads to increased oxidation. CECs then resist the sustained need for more ATP by increasing their mitochondrial mass, mitochondrial calcium and mitochondrial membrane potential. At this stage, CECs reach their maximum capacity and start to cope with irreversible oxidative damage, which leads to mitochondrial burnout. This burnout is accompanied by a dissipation of the membrane potential and a release of mitochondrial calcium, which in turn leads to cell death by apoptosis. The cornea is composed of three cellular layers, i.e. the epithelium, the stroma and the endothelium 1. The stroma needs to be maintained partially dehydrated to allow for the optimal arrangement of its collagen fibrils necessary to ensure its transparency 2. This ATP-demanding function is achieved mainly by the corneal endothelium, a leaky cell monolayer that pumps fluid out of the stroma, into the anterior chamber, maintaining the proper hydration of the corneal stroma 2,3. Fuchs endothelial corneal dystrophy (FECD) is characterized by a loss of corneal endothelial cells (CECs), abnormal extracellular matrix deposition on its basal membrane (Descemet's membrane) leading to the formation of excrescences called guttae, and changes in cellular morphology 4. The loss of CECs ultimately compromises the role of the endothelium to preserve corneal deturgescence. This leads to corneal edema and vision loss 4. FECD affects 4 percent of the US populations over 40 years old 5 and the only treatment currently available for FECD is corneal transplantation 6,7. Although the exact cause of FECD is not yet determined, there is growing evidence that oxidative stress and mitochondria are major contributors 8,9. The mechanism and the sequence of events leading to mitochondrial dysfunction and cell loss still remain to be elucidated. Manifestations of cumulative oxidative damage and mitochondrial dysfunction in ...

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“…Several reports suggest a strong association between mitochondrial DNA damage and aging [41]. Halilovic et al have shown that mechanism of endothelial cell death in FECD was due to increased generation of superoxide in mitochondria and loss of adenosine triphosphate (ATP) [42]. The same study also showed that oxidative DNA damage causes degeneration of endothelial cells in FECD.…”

Section: Rosmentioning

confidence: 95%

Oxidative Stress in the Pathogenesis of Corneal Endothelial Dystrophies and Other Corneal Diseases

Guha

Chaurasia

Roy

2018

ROS

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| Cornea being constantly exposed to sunlight and atmospheric oxygen is readily prone to oxidative damages. The functional antioxidant signaling helps maintain the levels of reactive oxygen species in the cells and keeps the cornea healthy. Corneal endothelial dystrophies include a group of corneal diseases that are marked by progressive degeneration of corneal endothelium leading to loss of vision. The increased level of oxidative stress in several corneal endothelial dystrophies indicates that there might be disruption in proper functioning of these signaling pathways. Various strategies to improve antioxidant signaling pathways may help develop novel clinical interventions to combat degeneration of endothelial cells that leads to vision loss. This review gives an overview of oxidative stress in the pathogenesis of corneal diseases.

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Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Cited by 68 publications

References 45 publications

Protective Effects Oncorneal Endothelium During Intracameral Irrigation Using N-(2)-l-alanyl-l-Glutamine

Protective Effects Oncorneal Endothelium During Intracameral Irrigation Using N-(2)-l-alanyl-l-Glutamine

Chronology of cellular events related to mitochondrial burnout leading to cell death in Fuchs endothelial corneal dystrophy

Oxidative Stress in the Pathogenesis of Corneal Endothelial Dystrophies and Other Corneal Diseases

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