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Mitochondrial fission and loss of cristae following exposure to elevated hydrostatic pressure. Differentiated RGC-5 cells were exposed to elevated hydrostatic pressure (30 mmHg) for 3 days and stained with MitoTracker Red. Non-pressurized control cells show a typical filamentous and fused mitochondrial network ( A ). Pressurized cells show mitochondrial fission, which is characterized by the conversion of tubular fused mitochondria into isolated small organelles ( B ). Electron micrographs of thin sections of RGC-5 cells show normal, elongated forms of mitochondria in non-pressurized control cells ( C ), whereas elevated hydrostatic pressure produces smaller mitochondria (arrow) and mitochondria with abnormal, severe cristae depletion (arrowheads; D ). Closely apposed smaller mitochondria were also observed, such as the six shown in panel E , suggesting that fission had occurred. To quantify the observation of severe cristae depletion in the mitochondria exposed to elevated hydrostatic pressure, the cristae density in tomographic volumes was determined after segmentation. This parameter was calculated by dividing the sum of the cristae volumes by the mitochondrial volume for each mitochondrion ( F ). There were 13 control (from two experiments) and 14 pressurized mitochondria (from two experiments) fully segmented into constituent compartments and analyzed (The asterisk indicates significance at p<0.001 compared to non-pressurized cells). Data represent the means±SD. Size bar represents 20 μm ( A and B ) and 500 nm ( C-E ).
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This study was conducted to determine whether elevated hydrostatic pressure alters mitochondrial structure, triggers release of the dynamin-related guanosine triphosphatase (GTPase) optic atrophy type 1 (OPA1) or cytochrome C from mitochondria, alters OPA1 gene expression, and can directly induce apoptotic cell death in cultured retinal ganglion ce...
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... C/D ratio related variables (examination-based CD, linear CD, and vertical CD) showed significant differences between the NTG and physiological cup groups (P < 0.05). People with NTG exhibited higher values for all three factors compared to those with physiological cup, which is consistent with the studies conducted by Weinreb 20 and Ju et al. 21 . The increased values of these variables in NTG can be attributed to the main mechanism of the disease, which involves optic nerve damage, optic disc atrophy, and cup enlargement. ...
Introduction: Glaucoma, a progressive eye disease associated with optic nerve damage and gradual vision loss, is primarily caused by elevated intraocular pressure. Increased pressure can lead to optic nerve compression and neuronal damage, resulting in visual impairment. Sometimes intraocular pressure is detected as being normal while optic nerve damage happens and cause increased C/D ration a variant called normotension glaucoma. This study aims to determine the frequency of Normotension Glaucoma (NTG) in patients with a high cup-to-disc ratio who were referred to the clinic.
... 54,55 Compression-induced downstream signaling is, however, not well understood to date, 57 although YAP and TAZ signaling are among suggested downstream cascades induced by compressive mechanostimulation, 57 which, in turn, affect the cells' ability to proliferate and undergo apoptosis, although these effects are largely dependent on the cell type. 97,[99][100][101][102][103] Additionally, compressive loads along with biochemical factors (interleukin-6) have also been shown to promote ECM remodeling while mediating epithelial-to-mesenchymal transition. 56 In adipocytes, compression was observed to trigger Wnt/ b-catenin signaling that, in turn, induces dedifferentiation of the cells, resulting in a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity (including osteogenesis, adipogenesis, myogenesis, chondrogenesis, and myofibrogenesis). ...
All cells possess an innate ability to respond to a range of mechanical stimuli through their complex internal machinery. This comprises various mechanosensory elements that detect these mechanical cues and diverse cytoskeletal structures that transmit the force to different parts of the cell, where they are transcribed into complex transcriptomic and signaling events that determine their response and fate. In contrast to static (or steady) mechanostimuli primarily involving constant-force loading such as compression, tension, and shear (or forces applied at very low oscillatory frequencies ( ≤ 1 Hz) that essentially render their effects quasi-static), dynamic mechanostimuli comprising more complex vibrational forms (e.g., time-dependent, i.e., periodic, forcing) at higher frequencies are less well understood in comparison. We review the mechanotransductive processes associated with such acoustic forcing, typically at ultrasonic frequencies ( > 20 kHz), and discuss the various applications that arise from the cellular responses that are generated, particularly for regenerative therapeutics, such as exosome biogenesis, stem cell differentiation, and endothelial barrier modulation. Finally, we offer perspectives on the possible existence of a universal mechanism that is common across all forms of acoustically driven mechanostimuli that underscores the central role of the cell membrane as the key effector, and calcium as the dominant second messenger, in the mechanotransduction process.
... 1,2 Most of these investigations utilized extrinsic forces to manipulate the intrinsic behavior of the cells through actomyosin contractility and cytoskeleton rearrangement, which can trigger biochemical signals depending on the dynamic nature of the force. 3−5 There are many different platforms to mimic in vivo physiological relevant forces experienced on cell cultures including substrate stiffness, 6,7 micro/nanopattering, 8−10 hydrostatic pressure, 11,12 perfusion flow, 13,14 shear forces, 15,16 compressive forces, 17−20 tensile forces, 21−23 and vibration. 24−26 The findings have led to the development of bioreactor systems for providing specific and complex mechanical environment used in tissue engineering and disease modeling. ...
... In this regard, the more promising neuroprotective approaches are based on the increase of antioxidant activities given that oxidative stress, like mitochondrial dysfunction, can be considered common denominators of all glaucoma forms [137]. In fact, the integrity of RGCs can be affected by an imbalance between ROS production and the inefficiency of antioxidant defenses, allowing mitochondrial dysfunction to play both a direct and indirect role in RGC apoptosis [138][139][140][141]. Thus, several therapeutic approaches have recently been focused on the protection of mitochondrial functions, as well as on the increasing of antioxidant systems, in order to protect the RGCs from damage and from the consequent risk of apoptosis activation. ...
Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the optic nerve. Glaucoma represents a group of neurodegenerative diseases where the slow progressive death of RGCs results in a permanent loss of vision. To date, although Intra Ocular Pressure (IOP) is considered the main therapeutic target, the precise mechanisms by which RGCs die in glaucoma have not yet been clarified. In fact, Primary Open Angle Glaucoma (POAG), which is the most common glaucoma form, also occurs without elevated IOP. This present review provides a summary of some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity and changes in pro-inflammatory cytokines along the RGC projection, all involved in the glaucoma cascade. Moreover, neuro-protective therapeutic approaches, which aim to improve RGC degeneration, have also been taken into consideration.
... Elevation of the IOP, at the lamina cribrosa or the optic nerve head (ONH) step, involves hypoperfusion and damages in reperfusion [28]. Increase in IOP is considered as a major factor of retinal ganglion cells (RGCs) dysfunction, leading to a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [29]. The etiology of POAG remains unclear but numerous risk factors have been shown as causes of its onset, including increased IOP, aging, gender, family history, OS, systemic and ocular vascular factors, and inflammation [30]. ...
Glaucoma is a progressive neurodegenerative disease that represents the major cause of irreversible blindness. Recent findings have shown which oxidative stress, inflammation, and glutamatergic pathway have main roles in the causes of glaucoma. Lithium is the major commonly used drug for the therapy of chronic mental illness. Lithium therapeutic mechanisms remain complex, including several pathways and gene expression, such as neurotransmitter and receptors, circadian modulation, ion transport, and signal transduction processes. Recent studies have shown that the benefits of lithium extend beyond just the therapy of mood. Neuroprotection against excitotoxicity or brain damages are other actions of lithium. Moreover, recent findings have investigated the role of lithium in glaucoma. The combination of lithium and atypical antipsychotics (AAPs) has been the main common choice for the treatment of bipolar disorder. Due to the possible side effects gradually introduced in therapy. Currently, no studies have focused on the possible actions of AAPs in glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with the overactivation of the GSK-3β signaling. The WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Lithium is correlated with upregulation the WNT/β-catenin pathway and downregulation of the GSK-3β activity. Thus, this review focuses on the possible actions of lithium and AAPs, as possible therapeutic strategies, on glaucoma and some of the presumed mechanisms by which these drugs provide their possible benefit properties through the WNT/β-catenin pathway.
... IOP elev cause of retinal ganglion cells (RGCs) damage, resulting in a retr ade and the accumulation of neurotrophic factors at the lamina cr ing the RGC soma [51]. The POAG etiology is still unclear but s been observed as the causes of promoting its onset, such as eleva ethnicity, first-degree family history of glaucoma, oxidative stre vascular factors, and inflammation [52]. ...
... IOP elevation is considered as a nal ganglion cells (RGCs) damage, resulting in a retrograde transport blockaccumulation of neurotrophic factors at the lamina cribrosa instead of reachsoma [51]. The POAG etiology is still unclear but several risk factors have ed as the causes of promoting its onset, such as elevated IOP, aging, gender, st-degree family history of glaucoma, oxidative stress, systemic and ocular ors, and inflammation [52]. ...
... IOP elevation is considered as a al ganglion cells (RGCs) damage, resulting in a retrograde transport blockccumulation of neurotrophic factors at the lamina cribrosa instead of reachsoma [51]. The POAG etiology is still unclear but several risk factors have d as the causes of promoting its onset, such as elevated IOP, aging, gender, t-degree family history of glaucoma, oxidative stress, systemic and ocular ors, and inflammation [52]. ...
Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway.
... Blood flow, oxygen supply, glucose utilization, and mitochondrial function are all important factors in considering energy metabolism and are all tightly interlinked with neuronal function and survival in the retina. Increased IOP and age, the other two main risk factors of glaucoma, are both directly correlated with increased ROS and impaired mitochondrial function [20,21]. Numerous studies suggest that the pathogenesis of glaucoma is potentially related to mitochondrial dysfunction. ...
Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic and ocular factors such as older age, lower ocular perfusion pressure, and intraocular pressure (IOP). Early signs of RGC damage comprise impairment of axonal transport, downregulation of specific genes and metabolic changes. The brain is often cited to be the highest energy-demanding tissue of the human body. The retina is estimated to have equally high demands. RGCs are particularly active in metabolism and vulnerable to energy insufficiency. Understanding the energy metabolism of the inner retina, especially of the RGCs, is pivotal for understanding glaucoma's pathophysiology. Here we review the key contributors to the high energy demands in the retina and the distinguishing features of energy metabolism of the inner retina. The major features of glaucoma include progressive cell death of retinal ganglions and optic nerve damage. Therefore, this review focuses on the energetic budget of the retinal ganglion cells, optic nerve and the relevant cells that surround them.
... Although further investigations are needed to clarify whether and how OPA1 variants could influence the development of glaucoma, it seems reasonable to lower intraocular pressure (IOP) to treat a patient with DOA with consistently elevated IOP and an already compromised optic nerve. This is further supported by the fact that elevated hydrostatic pressure in an in vitro cell model triggers detrimental mitochondrial changes similar to that of OPA1 +/− cells, including mitochondrial fission, abnormal cristae and release of pro-apoptotic molecules (Ju et al., 2009). ...
Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, which functions in many instances converge to OPA1 functions, were identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.
... Furthermore, entry of cells into and their motility in short confining channels, which compresses and stretches cells in the apicobasal and longitudinal direction, respectively, results in elevated RhoA activity and myosin II contractility . Moreover, when cells are subjected to sudden changes in hydraulic pressure, active responses by the cell are also observed (Ju et al., 2009;Stover and Nagatomi, 2007;Kao et al., 2017;Hui et al., 2014;Liu et al., 2019). These experiments, together with hydraulic resistance experiments in channels, indicate that cellular mechanosensation has a universal basis and involves membrane-tension-sensitive ion channels and Ca 2+ currents, as well as myosin and its associated pathways. ...
All mammalian cells live in the aqueous medium, yet for many cell biologists, water is a passive arena in which proteins are the leading players that carry out essential biological functions. Recent studies, as well as decades of previous work, have accumulated evidence to show that this is not the complete picture. Active fluxes of water and solutes of water can play essential roles during cell shape changes, cell motility and tissue function, and can generate significant mechanical forces. Moreover, the extracellular resistance to water flow, known as the hydraulic resistance, and external hydraulic pressures are important mechanical modulators of cell polarization and motility. For the cell to maintain a consistent chemical environment in the cytoplasm, there must exist an intricate molecular system that actively controls the cell water content as well as the cytoplasmic ionic content. This system is difficult to study and poorly understood, but ramifications of which may impact all aspects of cell biology from growth to metabolism to development. In this Review, we describe how mammalian cells maintain the cytoplasmic water content and how water flows across the cell surface to drive cell movement. The roles of mechanical forces and hydraulic pressure during water movement are explored.
... Therefore, IOP elevation is considered a direct or indirect cause of RGC damage, which results in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma. In addition to growth factor starvation, mitochondrial damage and glial cell activation, as well as oxidative stress, play an important role in promoting RGC apoptosis [7,8]. ...
Primary open-angle glaucoma (POAG) is the second leading cause of irreversible blindness worldwide. Increasing evidence suggests oxidative damage and immune response defects are key factors contributing to glaucoma onset. Indeed, both the failure of the trabecular meshwork tissue in the conventional outflow pathway and the neuroinflammation process, which drives the neurodegeneration, seem to be linked to the age-related over-production of free radicals (i.e., mitochondrial dysfunction) and to oxidative stress-linked immunostimulatory signaling. Several previous studies have described a wide range of oxidative stress-related makers which are found in glaucomatous patients, including low levels of antioxidant defences, dysfunction/activation of glial cells, the activation of the NF-κB pathway and the up-regulation of pro-inflammatory cytokines, and so on. However, the intraocular pressure is still currently the only risk factor modifiable by medication or glaucoma surgery. This present review aims to summarize the multiple cellular processes, which promote different risk factors in glaucoma including aging, oxidative stress, trabecular meshwork defects, glial activation response, neurodegenerative insults, and the altered regulation of immune response.
