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Mitochondrial Dysfunction in FECD
Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, heterogenous, age-related degenerative disease of corneal endothelial cells (CEnCs), occurring in the fifth decade of life with a higher incidence in females. It is characterized by extracellular matrix (ECM) protein deposition called corneal guttae, causing light glare and visual complaints in patients. In FECD, CEnCs exhibit stress-induced senescence, oxidative stress, DNA damage, heightened reactive oxygen species (ROS) production, mitochondrial damage, and dysfunction as well as sustained endoplasmic reticulum (ER) stress. Among all of these, mitochondrial dysfunction involving altered mitochondrial bioenergetics and dynamics plays a critical role in FECD pathogenesis.
The corneal endothelial is the innermost layer of the cornea and plays an important role in maintaining water balance and clarity of the cornea. Fuchs endothelial corneal dystrophy (FECD) is the most common corneal endothelial dystrophy. It is a bilateral, genetically heterogeneous degenerative disease of CEnCs occurring in 4% of the U.S. population over 40 years of age, with a higher incidence in women . It is characterized by the progressive decline of the CEnCs and the formation of extracellular matrix excrescences  in Descemet’s membrane (DM), called guttae, leading to corneal edema and loss of vision. Currently, the only treatment for FECD is corneal transplantation, which accounts for approximately 32,000 of the endothelial keratoplasties performed in the U.S. annually. It carries substantial economic and social burdens. Understanding the disease pathogenesis is essential for developing pharmacotherapeutic interventions to halt the disease. In FECD, CEnCs exhibits stress-induced senescence , oxidant-antioxidant imbalance , mitochondrial DNA damage  and dysfunction , sustained unfolded protein response (UPR) , and endoplasmic reticulum (ER) stress . Among these factors, mitochondrial stress  plays an important role in FECD pathogenesis. Maintaining functional mitochondria is the key to the ion pump function in CEnCs. Excessive damage to the mitochondria leads to its selective degradation called auto(mito)phagy .
2. Mitochondria in CEnCs
Due to many ion pumps and very active endothelial cell metabolism, mitochondrial density is very high in CEnCs, second only to retinal photoreceptors . Mitochondria, the powerhouse of the cells, regulate many physiological processes in CEnCs and play a pivotal role in their survival .
3. Mitochondrial DNA Damage in FECD
Mitochondrial DNA (mtDNA) damage occurs in many neurodegenerative disorders  such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. It also occurs in retinal diseases  such as age-related macular degeneration, diabetic retinopathy, glaucoma, and in corneal diseases  such as keratoconus, Kearns Sayre Syndrome, and FECD . In human FECD tissues, we found that 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidized DNA lesions, accumulated in mtDNA of CEnCs, suggesting increased oxidative mtDNA damage . Further studies using long-amplicon-quantitative polymerase chain reaction (LA-qPCR) demonstrated that human FECD specimens had significantly decreased small mitochondrial copy number and increased DNA lesion frequency (indicative of damage) than the normal specimens .
As Fuchs is prevalent in females , Liu et al. analyzed mtDNA damage in the mouse model of ultraviolet A (UVA)-induced FECD for both sexes and found that mtDNA damage was significantly more in the mouse corneal endothelial cells (MCEnCs) at week 4 and 8 post-UVA in females compared to males, suggesting the female susceptibility to FECD . However, mtDNA exhibited a similar extent of damage in both male and female mice at day 1 post-UVA, and it recovered at week 2 post-UVA .
For the in vitro studies, menadione (MN) induced oxidative stress to study mtDNA damage in normal (HCEnC-21T or HCECi: normal telomerase immortalized human corneal endothelial) and Fuchs (FECDi: immortalized FECD cell lines derived from FECD specimens) cell lines. Halilovic et al. demonstrated that the FECD cell line had significantly reduced the small mtDNA copy number compared to the normal control cell line and remained low in quantity after MN exposure . MtDNA damage was significantly greater in the control cell lines than the untreated control and remained significantly high in the FECD cell line after MN exposure . Miyajima et al. demonstrated a dysfunctional Nrf2-NQO1 axis, and specifically loss of NQO1 (NAD(P)H:quinone oxidoreductase 1) protein in FECD contributes to mitochondrial DNA damage and estrogen genotoxicity, explaining the higher incidence of FECD in females .
4. Mitochondrial Dysfunction in FECD
5. Autophagy and Mitophagy
6. Mechanisms of Mitophagy in FECD
7. Role of Mitophagy in FECD
The activation of mitophagy being detrimental or useful remains unclear in FECD. PINK1-Parkin mediated mitophagy, as described by our group, suggests that excessive mitophagy might destroy many normal mitochondrial, disturbing mitochondrial bioenergetics, and contributing to the cascade of destructive events in the pathogenesis of FECD. Therefore, therapeutics targeting mitophagy might not be beneficial in the late stage of FECD. However, it might be advantageous in the earlier stages of FECD as CEnCs might alleviate some intracellular mitochondrial stress by removing damaged mitochondria via mitophagy.
The entry is from 10.3390/cells10081888
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