scholarly journals Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1888
Author(s):  
Varun Kumar ◽  
Ula V. Jurkunas
Keyword(s):  
Mitochondrial Dysfunction ◽  
Treatment Options ◽  
Critical Role ◽  
Corneal Transplantation ◽  
Cell Loss ◽  
Corneal Dystrophy ◽  
Mitochondrial Damage ◽  
Extreme Stress ◽  
Age Related ◽  
Visual Complaints

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. Corneal transplantation is the only treatment option for FECD patients, which imposes a substantial socioeconomic burden. 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. Extreme stress initiates mitochondrial damage, leading to activation of autophagy, which involves clearance of damaged mitochondria called auto(mito)phagy. In this review, we discuss the role of mitochondrial dysfunction and mitophagy in FECD. This will provide insights into a novel mechanism of mitophagy in post-mitotic ocular cell loss and help us explore the potential treatment options for FECD.

scholarly journals Neuroinflammatory Mechanisms of Mitochondrial Dysfunction and Neurodegeneration in Glaucoma

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Joao N. Duarte
Keyword(s):  
Mitochondrial Dysfunction ◽  
Autosomal Dominant ◽  
Cell Loss ◽  
Mitochondrial Damage ◽  
Retinal Ganglion ◽  
Dna Mutations ◽  
Age Related ◽  
Species Production ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

The exact mechanism of retinal ganglion cell loss in the pathogenesis of glaucoma is yet to be understood. Mitochondrial damage-associated molecular patterns (DAMPs) resulting from mitochondrial dysfunction have been linked to Leber’s hereditary optic neuropathy and autosomal dominant optic atrophy, as well as to brain neurodegenerative diseases. Recent evidence shows that, in conditions where mitochondria are damaged, a sustained inflammatory response and downstream pathological inflammation may ensue. Mitochondrial damage has been linked to the accumulation of age-related mitochondrial DNA mutations and mitochondrial dysfunction, possibly through aberrant reactive oxygen species production and defective mitophagy. The present review focuses on how mitochondrial dysfunction may overwhelm the ability of neurons and glial cells to adequately maintain homeostasis and how mitochondria-derived DAMPs trigger the immune system and induce neurodegeneration.

scholarly journals Mitochondrial Redox Signaling Is Critical to the Normal Functioning of the Neuronal System

2021 ◽  
Vol 9 ◽  
Author(s):  
Olena Odnokoz ◽  
Kyle Nakatsuka ◽  
Corbin Wright ◽  
Jovelyn Castellanos ◽  
Vladimir I. Klichko ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Neurological Disorders ◽  
Critical Role ◽  
Redox Balance ◽  
Causal Link ◽  
Temperature Sensitive ◽  
Neural Function ◽  
Neuronal System ◽  
Age Related

Mitochondrial dysfunction often leads to neurodegeneration and is considered one of the main causes of neurological disorders, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other age-related diseases. Mitochondrial dysfunction is tightly linked to oxidative stress and accumulating evidence suggests the association between oxidative stress and neurological disorders. However, there is insufficient knowledge about the role of pro-oxidative shift in cellular redox and impairment of redox-sensitive signaling in the development of neurodegenerative pathological conditions. To gain a more complete understanding of the relationship between mitochondria, redox status, and neurodegenerative disorders, we investigated the effect of mitochondrial thiol-dependent peroxidases, peroxiredoxins (Prxs), on the physiological characteristics of flies, which change with pathologies such as PD, ALS and during aging. We previously found that through their ability to sense changes in redox and regulate redox-sensitive signaling, Prxs play a critical role in maintaining global thiol homeostasis, preventing age-related apoptosis and chronic activation of the immune response. We also found that the phenotype of flies under-expressing Prxs in mitochondria shares many characteristics with the phenotype of Drosophila models of neurological disorders such as ALS, including impaired locomotor activity and compromised redox balance. Here, we expanded the study and found that under-expression of mitochondrial Prxs leads to behavioral changes associated with neural function, including locomotor ability, sleep-wake behavior, and temperature-sensitive paralysis. We also found that under-expression of mitochondrial Prxs with a motor-neuron-specific driver, D42-GAL4, was a determining factor in the development of the phenotype of shortened lifespan and impaired motor activity in flies. The results of the study suggest a causal link between mitochondrial Prx activity and the development of neurological disorders and pre-mature aging.

scholarly journals Antimycin A-Induced Mitochondrial Damage Causes Human RPE Cell Death despite Activation of Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Hytti ◽  
Eveliina Korhonen ◽  
Juha M. T. Hyttinen ◽  
Heidi Roehrich ◽  
Kai Kaarniranta ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mitochondrial Damage ◽  
Age Related Macular Degeneration ◽  
Complex Iii ◽  
Antimycin A ◽  
Age Related ◽  
And Function

Mitochondrial dysfunction has been implicated in a wide variety of degenerative diseases, including age-related macular degeneration. Damage to mitochondria and mitochondrial DNA accumulates with age in the postmitotic retinal pigment epithelium (RPE), which could lead to RPE cell death and trigger disease. One possible mechanism for cells to avoid cell death is mitophagy, the targeted clearance of damaged mitochondria by autophagy. Here, we induced mitochondrial damage in human RPE cells (ARPE-19 and hRPE), using antimycin A, an inhibitor of complex III of the electron transport chain, and investigated cellular viability, mitochondrial structure and function, and autophagy activity. We observed that antimycin A evoked dose-dependent cell death, a rapid loss in mitochondrial membrane potential, and a collapse of oxidative phosphorylation. Mitochondria appeared swollen and there was clear damage to their cristae structure. At the same time, cells were undergoing active autophagy and were sensitive to autophagy inhibition by bafilomycin A1 or chloroquine. These results indicate that mitochondrial dysfunction can cause significant RPE damage and that autophagy is an important survival mechanism for cells suffering from mitochondrial damage.

scholarly journals Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

2016 ◽  
Vol 113 (16) ◽  
pp. E2231-E2240 ◽  
Author(s):  
Danny Bavli ◽  
Sebastian Prill ◽  
Elishai Ezra ◽  
Gahl Levy ◽  
Merav Cohen ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Real Time ◽  
Critical Role ◽  
Mitochondrial Damage ◽  
Mitochondrial Activity ◽  
Prognostic Information ◽  
Mitochondrial Stress ◽  
Cellular Adaptation ◽  
Chip Technology ◽  
On Chip

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liver-on-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.

Cardiac mitochondrial bioenergetics, oxidative stress, and aging

2007 ◽  
Vol 292 (6) ◽  
pp. C1983-C1992 ◽  
Author(s):  
Sharon Judge ◽  
Christiaan Leeuwenburgh
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Caloric Restriction ◽  
Critical Role ◽  
Antioxidant Enzyme Activities ◽  
Theories Of Aging ◽  
Age Related ◽  
Interfibrillar Mitochondria ◽  
Oxidant Production ◽  
Subsarcolemmal Mitochondria

Mitochondria have been a central focus of several theories of aging as a result of their critical role in bioenergetics, oxidant production, and regulation of cell death. A decline in cardiac mitochondrial function coupled with the accumulation of oxidative damage to macromolecules may be causal to the decline in cardiac performance with age. In contrast, regular physical activity and lifelong caloric restriction can prevent oxidative stress, delay the onset of morbidity, increase life span, and reduce the risk of developing several pathological conditions. The health benefits of life long exercise and caloric restriction may be, at least partially, due to a reduction in the chronic amount of mitochondrial oxidant production. In addition, the available data suggest that chronic exercise may serve to enhance antioxidant enzyme activities, and augment certain repair/removal pathways, thereby reducing the amount of oxidative tissue damage. However, the characterization of age-related changes to cardiac mitochondria has been complicated by the fact that two distinct populations of mitochondria exist in the myocardium: subsarcolemmal mitochondria and interfibrillar mitochondria. Several studies now suggest the importance of studying both mitochondrial populations when attempting to elucidate the contribution of mitochondrial dysfunction to myocardial aging. The role that mitochondrial dysfunction and oxidative stress play in contributing to cardiac aging will be discussed along with the use of lifelong exercise and calorie restriction as countermeasures to aging.

scholarly journals The Relationship between Mitochondria and Neurodegeration in the Eye: A Review

2021 ◽  
Vol 11 (16) ◽  
pp. 7385
Author(s):  
Hongtao Liu ◽  
Hanhan Liu ◽  
Verena Prokosch
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Mitochondrial Damage ◽  
Age Related Macular Degeneration ◽  
Post Injury ◽  
Injury Repair ◽  
Age Related ◽  
The Relationship

Mitochondria are the energy factories of cells. Mitochondrial dysfunction directly affects the function and morphology of cells. In recent years, growing evidence has shown that mitochondrial dysfunction plays an important role in neurodegenerative diseases. In the eye, some age-related diseases are considered to be neurodegenerative diseases, such as primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). Here, we review the mechanisms of mitochondrial damage, post-injury repair, and the roles of mitochondria in various tissues of the eye. In the following sections, the potential for treating glaucoma by reducing mitochondrial damage and promoting post-injury repair is also discussed.

Oxidative Stress, Ocular Disease and Diabetes Retinopathy

2019 ◽  
Vol 24 (40) ◽  
pp. 4726-4741 ◽  
Author(s):  
Orathai Tangvarasittichai ◽  
Surapon Tangvarasittichai
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Death ◽  
Protein Modification ◽  
Morphological Changes ◽  
Corneal Dystrophy ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Retinal Light Damage ◽  
Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 846-859
Author(s):  
Mohd Saeed ◽  
Mohd Adnan Kausar ◽  
Rajeev Singh ◽  
Arif J. Siddiqui ◽  
Asma Akhter
Keyword(s):  
Protein Misfolding ◽  
Covalent Binding ◽  
Critical Role ◽  
Enzymatic Reaction ◽  
Treatment Strategies ◽  
Bioactive Molecules ◽  
Carbonyl Stress ◽  
Defense System ◽  
Pathological Conditions ◽  
Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

Pathogenesis of Age-related Cataract: a systematic review of proteomic studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Christina Karakosta ◽  
Argyrios Tzamalis ◽  
Michalis Aivaliotis ◽  
Ioannis Tsinopoulos
Keyword(s):  
Systematic Review ◽  
Oxidant Stress ◽  
Critical Role ◽  
Human Lens ◽  
Nuclear Cataract ◽  
Cataract Formation ◽  
Post Translational Modification ◽  
Ability To Act ◽  
Age Related

Background/Objective:: The aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens. Materials and Methods:: We searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses. Results:: Deamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7. Conclusion:: D-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in human, while the role of oxidant stress in age-related cataract formation is dominant.

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