Role of glycolysis in retinal vascular endothelium, glia, pigment epithelium, and photoreceptor cells and as therapeutic targets for related retinal diseases

Glycolysis produces large amounts of adenosine triphosphate (ATP) in a short time. The retinal vascular endothelium feeds itself primarily through aerobic glycolysis with less ATP. But when it generates new vessels, aerobic glycolysis provides rapid and abundant ATP support for angiogenesis, and thus inhibition of glycolysis in endothelial cells can be a target for the treatment of neovascularization. Aerobic glycolysis has a protective effect on Müller cells, and it can provide with a target for visual protection and maintenance of the blood-retinal barrier. Under physiological conditions, the mitochondria of RPE can use lactic acid produced by photoreceptor cells as an energy source to provide ATP for survival. In pathological conditions, because RPE cells avoid their oxidative damage by increasing glycolysis, a large number of glycolysis products accumulate, which in turn has a toxic effect on photoreceptor cells. This shows that stabilizing the function of RPE mitochondria may become a target for the treatment of diseases such as retinal degeneration. The decrease of aerobic glycolysis leads to the decline of photoreceptor cell function and impaired vision; therefore, aerobic glycolysis of stable photoreceptor cells provides a reliable target for delaying vision loss. It is of great significance to study the role of glycolysis in various retinal cells for the targeted treatment of ocular fundus diseases.

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A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface

Communications Biology ◽

10.1038/s42003-021-01682-5 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Cynthia Tang ◽

Jimin Han ◽

Sonal Dalvi ◽

Kannan Manian ◽

Lauren Winschel ◽

...

Keyword(s):

Photoreceptor Cell ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cell Loss ◽

Human Model ◽

Lysosomal Storage ◽

Rpe Cells ◽

Cln3 Disease

AbstractMutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy.

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Oxidative stress-mediated TXNIP loss causes RPE dysfunction

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0327-y ◽

2019 ◽

Vol 51 (10) ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Min Ji Cho ◽

Sung-Jin Yoon ◽

Wooil Kim ◽

Jongjin Park ◽

Jangwook Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Function ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Common Factor ◽

Age Related Macular Degeneration ◽

Autophagic Flux ◽

Blood Retinal Barrier ◽

Rpe Cells ◽

Age Related

Abstract The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood–retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.

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Inhibition of mitochondrial fission preserves photoreceptors after retinal detachment

10.1101/197467 ◽

2017 ◽

Author(s):

Xiangjun She ◽

Xinmin Lu ◽

Tong Li ◽

Junran Sun ◽

Jian Liang ◽

...

Keyword(s):

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Mitochondrial Fission ◽

Critical Role ◽

Photoreceptor Degeneration ◽

Apoptotic Pathway ◽

Neurosensory Retina

AbstractPhotoreceptor degeneration is a leading cause of visual impairment worldwide. Separation of neurosensory retina from the underlying retinal pigment epithelium is a prominent feature preceding photoreceptor degeneration in a variety of retinal diseases. Although ophthalmic surgeries have been well developed to restore retinal structures, post-op patients usually experience progressive photoreceptor degeneration and irreversible vision loss that is incurable at present. Previous studies point to a critical role of mitochondria-mediated apoptotic pathway in photoreceptor degeneration, but the upstream triggers remain largely unexplored. In this study, we show that after experimental RD induction, photoreceptors activate dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway and subsequent apoptotic cascades. Mechanistically, endogenous ROS is necessary for Drp1 activation in vivo and exogenous ROS insult is sufficient to activate Drp1-dependent mitochondrial fission in cultured photoreceptors. Accordingly, inhibition of Drp1 activity effectively preserves mitochondrial integrity and rescues photoreceptors. Collectively, our data delineates a ROS-Drp1-mitochondria axis that promotes photoreceptor degeneration in retinal diseased models.

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The role of the vascular endothelium in arenavirus haemorrhagic fevers

Thrombosis and Haemostasis ◽

10.1160/th09-06-0357 ◽

2009 ◽

Vol 102 (12) ◽

pp. 1024-1029 ◽

Cited By ~ 27

Author(s):

Stefan Kunz

Keyword(s):

Vascular Endothelium ◽

Cell Function ◽

Experimental Studies ◽

Lassa Fever ◽

Vascular Involvement ◽

Lassa Virus ◽

South American ◽

The South ◽

Endothelial Cell Function

SummaryViral haemorrhagic fevers (VHF) caused by arenaviruses are among the most devastating emerging human diseases.The most important pathogen among the arenaviruses is Lassa virus (LASV), the causative agent of Lassa fever that is endemic to West Africa. On the South American continent, the New World arenavirus Junin virus (JUNV), Machupo (MACV), Guanarito (GTOV), and Sabia virus (SABV) have emerged as causative agents of severe VHFs. Clinical and experimental studies on arenavirus VHF have revealed a crucial role of the endothelium in their pathogenesis. However, in contrast to other VHFs, haemorrhages are not a salient feature of Lassa fever and fatal cases do not show overt destruction of vascular tissue.The functional alteration of the vascular endothelium that precede shock and death in fatal Lassa fever may be due to more subtle direct or indirect effects of the virus on endothelial cells. Haemorrhagic disease manifestations and vascular involvement are more pronounced in the VHF caused by the South American haemorrhagic fever viruses. Recent studies on JUNV revealed perturbation of specific endothelial cell function, including expression of cell adhesion molecules, coagulation factors, and vasoactive mediators as a consequence of productive viral infection.These studies provided first possible links to some of the vascular abnormalities observed in patients; however, their relevance in vivo remains to be investigated.

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Role of Peoxisome Proliferator Activator Receptor on Blood Retinal Barrier Breakdown

PPAR Research ◽

10.1155/2008/679237 ◽

2008 ◽

Vol 2008 ◽

pp. 1-4 ◽

Cited By ~ 6

Author(s):

Yasuo Yanagi

Keyword(s):

Diabetic Retinopathy ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Critical Role ◽

Blood Retinal Barrier ◽

Early Diabetes ◽

Pathological Conditions ◽

Barrier Breakdown ◽

Brb Breakdown

The retinal vessels have two barriers: the retinal pigment epithelium and the retinal vascular endothelium. Each barrier exhibits increased permeability under various pathological conditions. This condition is referred to as blood retinal barrier (BRB) breakdown. Clinically, the most frequently encountered condition causing BRB breakdown is diabetic retinopathy. In recent studies, inflammation has been linked to BRB breakdown and vascular leakage in diabetic retinopathy. Biological support for the role of inflammation in early diabetes is the adhesion of leukocytes to the retinal vasculature (leukostasis) observed in diabetic retinopathy. is a member of a ligand-activated nuclear receptor superfamily and plays a critical role in a variety of biological processes, including adipogenesis, glucose metabolism, angiogenesis, and inflammation. There is now strong experimental evidence to support the theory that inhibits diabetes-induced retinal leukostasis and leakage, playing an important role in the pathogenesis of diabetic retinopathy. Therapeutic targeting of may be beneficial to diabetic retinopathy.

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Iron Overload in Diabetic Retinopathy: A Cause or a Consequence of Impaired Mechanisms?

Experimental Diabetes Research ◽

10.1155/2010/714108 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Andreea Ciudin ◽

Cristina Hernández ◽

Rafael Simó

Keyword(s):

Diabetic Retinopathy ◽

Iron Overload ◽

Iron Homeostasis ◽

Cell Function ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Renin Angiotensin System ◽

Retinal Neurodegeneration ◽

Novel Therapeutic Strategies

Iron is an essential ion for life, playing a central role in many metabolic processes. The most important property of free iron is its capacity to be reversibly oxidized and reduced, but at same time this make it highly pro-oxidant molecule. In this regard, iron is able to generate powerful reactive oxygen species (ROS). For this reason, careful control on iron availability is central to the maintenance of normal cell function in the retina. In the diabetic eye there is an impairment of iron homeostasis, thus leading to iron overload. The mechanisms involved in this process include: (1) Destruction of heme molecules induced by hyperglycemia (2) Intraretinal and vitreal hemorrhages (3) Overexpression of the renin-angiotensin system. The main consequences of iron overload are the following: (1) Retinal neurodegeneration due to the increase of oxidative stress (2) Increase of AGE-RAGE binding (3) Defective phagocytosis of retinal pigment epithelium, which generates the accumulation of autoantigens and the synthesis of proinflammatory cytokines. Further studies addressed to explore not only the role of iron in the pathogenesis of diabetic retinopathy, but also to design novel therapeutic strategies based on the regulation of iron homeostasis are needed.

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Role of Extracellular Mycobacteria in Blood-Retinal Barrier Invasion in a Zebrafish Model of Ocular TB

Pathogens ◽

10.3390/pathogens10030333 ◽

2021 ◽

Vol 10 (3) ◽

pp. 333

Author(s):

Santhosh Kumar Damera ◽

Ranjan Kumar Panigrahi ◽

Sanchita Mitra ◽

Soumyava Basu

Keyword(s):

Immune Cells ◽

Vascular Endothelium ◽

Intraocular Inflammation ◽

Post Injection ◽

Blood Retinal Barrier ◽

Zebrafish Model ◽

Course Of Disease ◽

Retinal Tissue ◽

Ocular Tb

Intraocular inflammation following mycobacterial dissemination to the eye is common in tuberculosis (TB)-endemic countries. However, the early host–pathogen interactions during ocular dissemination are unknown. In this study, we investigated the early events during mycobacterial invasion of the blood-retinal barriers (BRBs) with fluorescent-tagged Mycobacterium marinum (Mm), host macrophages, and retinal vasculature in a zebrafish model of ocular TB. We found that Mm invaded the vascular endothelium in either the extracellular or intracellular (inside phagocytes) state, typically 3–4 days post-injection (dpi). Extracellular Mm are phagocytosed in the retinal tissue and progress to form a compact granuloma around 6 dpi. Intracellular Mm crossing the BRBs are likely to be less virulent and either persist inside solitary macrophages (in most cases) or progress to loosely arranged granuloma (rarely). The early interactions between mycobacteria and host immune cells can thus determine the course of disease during mycobacterial dissemination to the eye.

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Hexokinase 2 is dispensable for photoreceptor development but is required for survival during aging and outer retinal stress

10.1101/782607 ◽

2019 ◽

Author(s):

Eric Weh ◽

Zuzanna Lutrzykowska ◽

Andrew Smith ◽

Heather Hager ◽

Mercy Pawar ◽

...

Keyword(s):

Retinal Detachment ◽

Vision Loss ◽

Aerobic Glycolysis ◽

Metabolic Stress ◽

Hexokinase 2 ◽

Akt Phosphorylation ◽

Acute And Chronic Stress ◽

Enzymatic Function ◽

And Function

AbstractPhotoreceptor death is the ultimate cause of vision loss in many retinal degenerative conditions. Identifying novel therapeutic avenues for prolonging photoreceptor health and function has the potential to improve vision and quality of life for patients suffering from degenerative retinal disorders. Photoreceptors are metabolically unique among other neurons in that they process the majority of their glucose via aerobic glycolysis. One of the main regulators of aerobic glycolysis is hexokinase 2 (HK2). Beyond its enzymatic function of phosphorylating glucose to glucose-6-phosphate, HK2 has additional non-enzymatic roles, including the regulation of apoptotic signaling via AKT signaling. Determining the role of HK2 in photoreceptor homeostasis may identify novel signaling pathways that can be targeted with neuroprotective agents to boost photoreceptor survival during metabolic stress. Here we show that following experimental retinal detachment, p-AKT is upregulated and HK2 translocates to mitochondria. Inhibition of AKT phosphorylation in 661W photoreceptor-like cells results in translocation of mitochondrial HK2 to the cytoplasm, increased caspase activity, and decreased cell viability. Rod-photoreceptors lacking HK2 upregulate HK1 and appear to develop normally. Interestingly, we found that HK2-deficient photoreceptors are more susceptible to acute nutrient deprivation in the experimental retinal detachment model. Additionally, HK2 appears to be important for preserving photoreceptors during aging. We show that retinal glucose metabolism is largely unchanged after HK2 deletion, suggesting that the non-enzymatic role of HK2 is important for maintaining photoreceptor health. These results suggest that HK2 expression is critical for preserving photoreceptors during acute nutrient stress and aging. More specifically, p-AKT mediated translocation of HK2 to the mitochondrial surface may be critical for protecting photoreceptors from acute and chronic stress.

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Role of extracellular mycobacteria in blood-retinal barrier invasion in a zebrafish model of ocular TB

10.1101/2021.01.08.425865 ◽

2021 ◽

Author(s):

Santhosh Kumar Damera ◽

Ranjan Kumar Panigrahi ◽

Sanchita Mitra ◽

Soumyava Basu

Keyword(s):

Immune Cells ◽

Vascular Endothelium ◽

Intraocular Inflammation ◽

Post Injection ◽

Blood Retinal Barrier ◽

Zebrafish Model ◽

Course Of Disease ◽

Retinal Tissue ◽

Ocular Tb

Intraocular inflammation following mycobacterial dissemination to the eye is common in tuberculosis (TB)-endemic countries. However, the early host-pathogen interactions during ocular dissemination are unknown. In this study, we investigate the early events during mycobacterial invasion of the blood-retinal barriers (BRB) with fluorescent tagged Mycobacterium marinum ( Mm ), host macrophages and retinal vasculature in a zebrafish model of ocular TB. We found that Mm invaded the vascular endothelium either in extracellular or intracellular (inside phagocytes) state, typically 3-4 days post-injection (dpi). Extracellular Mm are phagocytosed in the retinal tissue, and progress to form a compact granuloma around 6 dpi. Intracellular Mm crossing the BRB are likely to be less virulent, and either persist inside solitary macrophages (most cases), or progress to loosely arranged granuloma (rare). The early interactions between mycobacteria and host immune cells can thus determine the course of disease during mycobacterial dissemination to the eye.

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Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors

10.1101/2021.02.04.429634 ◽

2021 ◽

Author(s):

Louis M Scott ◽

Emma E Vincent ◽

Natalie Hudson ◽

Chris Neal ◽

Nicholas Jones ◽

...

Keyword(s):

Mitochondrial Respiration ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Metabolic Reprogramming ◽

Mitochondrial Morphology ◽

Interleukin 33 ◽

Stress Signals

SummaryIt remains unresolved how retinal pigment epithelial (RPE) cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed RPE to several stress signals, particularly toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonises the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular “alarmin” activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declines and resultant bioenergetic switching is aligned with altered mitochondrial morphology. Our data not only sheds new light in the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors, but also uncovers a novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.

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