bims-mideyd 2023-01-29 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2023‒01‒29
eight papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Cysteinyl leukotriene receptor 1 is a potent regulator of the endosomal-lysosomal system in the ARPE-19 retinal pigment epithelial cell line.
Lutein nanodisks protect human retinal pigment epithelial cells from UV light-induced damage.
Calpain-2 Facilitates Autophagic/Lysosomal Defects and Apoptosis in ARPE-19 Cells and Rats Induced by Exosomes from RPE Cells under NaIO3 Stimulation.
Galanin receptor 3 - A new pharmacological target in retina degeneration.
A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumor necrosis factor α.
Degeneration of retina-brain components and connections in glaucoma: Disease causation and treatment options for eyesight preservation.
NAD salvage pathway machinery expression in normal and glaucomatous retina and optic nerve.
Autophagy and senescence of rat retinal precursor cells under high glucose.

Traffic. 2023 Jan 27.

Cysteinyl leukotriene receptor 1 is a potent regulator of the endosomal-lysosomal system in the ARPE-19 retinal pigment epithelial cell line.

Andreas Koller, Susanne Maria Brunner, Julia Preishuber-Pflügl, Christian Runge, Anja-Maria Ladek, Herbert Anton Reitsamer, Andrea Trost.

  The endosomal-lysosomal system is central for cell homeostasis and comprises the functions and dynamics of particular organelles including endosomes, lysosomes and autophagosomes. In previous studies, we found that the cysteinyl leukotriene receptor 1 (CysLTR1) regulates autophagy in the retinal pigment epithelial cell line ARPE-19 under basal cellular conditions. However, the underlying mechanism by which CysLTR1 regulates autophagy is unknown. Thus, in the present study, the effects of CysLTR1 inhibition on the endosomal-lysosomal system are analyzed in detail to identify the role of CysLTR1 in cell homeostasis and autophagy regulation. CysLTR1 inhibition in ARPE-19 cells by Zafirlukast, a CysLTR1 antagonist, depleted the lysosomal pool. Furthermore, CysLTR1 antagonization reduced endocytic capacity and internalization of epidermal growth factor and decreased levels of the transferrin receptor, CD71. Serum starvation abolished the effect of Zafirlukast on the autophagic flux, which identifies the endocytic regulation of serum components by CysLTR1 as an important autophagy-modulating mechanism. The role of CysLTR1 in inflammation and cell stress has been exceedingly studied, but its involvement in the endosomal-lysosomal pathway is largely unknown. This current study provides new insights into basal activity of CysLTR1 on cellular endocytosis and the subsequent impact on downstream processes like autophagy. This article is protected by copyright. All rights reserved.

Keywords:  CysLTR1; EGF endocytosis; Zafirlukast; autophagy; endosomal-lysosomal system; retinal pigment epithelial cells

DOI:  https://doi.org/10.1111/tra.12881
Front Nanotechnol. 2022 ;pii: 955022. [Epub ahead of print]4

Lutein nanodisks protect human retinal pigment epithelial cells from UV light-induced damage.

Anthony Moschetti, Colin A Fox, Samuel McGowen, Robert O Ryan.

  The hydrophobic carotenoid, lutein, was conferred with aqueous solubility upon formulation into reconstituted discoidal high density lipoprotein particles, termed lutein nanodisks (ND). When formulated with phosphatidylcholine (PC), apolipoprotein (apo) A-I and lutein (formulation ratio = 5 mg PC/2 mg apoA-I/1 mg lutein), lutein solubilization efficiency in phosphate buffered saline (PBS) was ~90%. The UV/Vis absorbance maxima for lutein ND in PBS were red shifted by 6-13 nm versus the corresponding lutein absorbance maxima in ethanol. FPLC gel filtration chromatography gave rise to a single major absorbance peak in the size range of ND. Incubation of cultured ARPE-19 cells with lutein ND resulted in lutein uptake, as determined by HPLC analysis of cell extracts. Compared to control incubations, ARPE-19 cells incubated with lutein ND were protected from UV light-induced loss of cell viability. Consistent with this, reactive oxygen species generation, induced by exposure to UV irradiation, was lower in lutein-enriched cells than in control cells. Thus, uptake of ND-associated lutein protects ARPE-19 cells from UV light-induced damage. Taken together, the data indicate ND provide an aqueous lutein delivery vehicle for biotechnological or therapeutic applications.

Keywords:  UV irradiation; lutein; macular degeneration; nanodisc; retinal pigment epithelial cells

DOI:  https://doi.org/10.3389/fnano.2022.955022
Oxid Med Cell Longev. 2023 ;2023 3310621

Calpain-2 Facilitates Autophagic/Lysosomal Defects and Apoptosis in ARPE-19 Cells and Rats Induced by Exosomes from RPE Cells under NaIO3 Stimulation.

Shuaishuai Zhang, Yingzhe Qiu, Yuan Feng, Yi Zhang, Yanan Li, Boxin Wang, Heliang Wei, Xilong Chen, Lixia Shen, Wei Li, Liqing Zheng, Yuanyuan Zhang.

Although accumulated evidence supports the notion that calpain contributes to eye disease, the mechanisms by which calpain promotes RPE injury are not defined. The present study is aimed at investigating whether the effect of NaIO3-exos (exosomes derived from RPE cells under NaIO3 stimulation) on the dysfunction of the autophagy-lysosomal pathway (ALP) and apoptosis is based on its regulation of calpain activation in ARPE-19 cells and rats. The results showed that calpain-2 activation, ALP dysfunction, and apoptosis were induced by NaIO3-exos in ARPE-19 cells. NaIO3-exo significantly increased autophagic substrates by activating lysosomal dysfunction. ALP dysfunction and apoptosis in vitro could be eliminated by knocking down calpain-2 (si-C2) or the inhibitor calpain-2-IN-1. Further studies indicated that NaIO3-exo enhanced calpain-2 expression, ALP dysfunction, apoptosis, and retinal damage in rats. In summary, these results demonstrate for the first time that calpain-2 is one of the key players in the NaIO3-exo-mediated ALP dysfunction, apoptosis, and retinal damage and identify calpain-2 as a promising target for therapies aimed at age-related macular degeneration (AMD).

DOI: https://doi.org/10.1155/2023/3310621
Pharmacol Res. 2023 Jan 21. pii: S1043-6618(23)00031-2. [Epub ahead of print]188 106675

Galanin receptor 3 - A new pharmacological target in retina degeneration.

Joseph T Ortega, Tanu Parmar, Beata Jastrzebska.

  The neuropeptide galanin receptor 3 (GALR3) is a class A G protein-coupled receptor (GPCR) broadly expressed in the nervous system, including the retina. GALR3 is involved in the modulation of immune and inflammatory responses. Tight control of these processes is critical for maintaining homeostasis in the retina and is required to sustain vision. Here, we investigated the role of GALR3 in retina pathologies triggered by bright light and P23H mutation in the rhodopsin (RHO) gene, associated with the activation of oxidative stress and inflammatory responses. We used a multiphase approach involving pharmacological inhibition of GALR3 with its antagonist SNAP-37889 and genetic depletion of GALR3 to modulate the GALR3 signaling. Our in vitro experiments in the retinal pigment epithelium-derived cells (ARPE19) susceptible to all-trans-retinal toxicity indicated that GALR3 could be involved in the cellular stress response to this phototoxic product. Indeed, blocking the GALR3 signaling in Abca4-/-/Rdh8-/- and wild-type Balb/cJ mice, sensitive to bright light-induced retina damage, protected retina health in these mice exposed to light. The retina morphology and function were substantially improved, and stress response processes were reduced in these mouse models compared to the controls. Furthermore, in P23H Rho knock-in mice, a model of retinitis pigmentosa (RP), both pharmacological inhibition and genetic ablation of GALR3 prolonged the survival of photoreceptors. These results indicate that GALR3 signaling contributes to acute light-induced and chronic RP-linked retinopathies. Together, this work provides the pharmacological knowledge base to evaluate GALR3 as a potential target for developing novel therapies to combat retinal degeneration.

Keywords:  Galanin receptors; Neuroinflammation; Photoreceptor; Retinal degeneration

DOI:  https://doi.org/10.1016/j.phrs.2023.106675
FEBS J. 2023 Jan 27.

A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumor necrosis factor α.

Zuberwasim Sayyad, Sreeram Kaveti, Debanjan Bhattacharjee, Dhiviya Vedagiri, Nishant Jain, Ghanshyam Swarup.

  Optineurin/OPTN polymorphism, M98K is associated with normal tension glaucoma in certain populations, and genetic evidence shows its interaction with tumor necrosis factor alpha (TNFα) polymorphism in causing glaucoma. Endoplasmic reticulum (ER) stress is also associated with glaucoma. We hypothesized that M98K-OPTN may sensitize retinal ganglion cells to various types of stress. To test this hypothesis, stable clones of a retinal cell line, 661W, expressing either wild-type (WT)-OPTN or M98K-OPTN were generated, and examined for their survival under various stress conditions. Compared to WT-OPTN expressing cells, M98K-OPTN expressing cells showed significantly lower cell survival and higher activation of caspase 3 and caspase 8 upon treatment with tunicamycin (an inducer of ER stress) or TNFα. Levels of ER stress sensors IRE1α, PERK and ATF6, were significantly higher in M98K-OPTN expressing cells. Tunicamycin treatment resulted in significantly higher induction of ER stress marker CHOP, and several other ER stress response genes regulated by IRE1α-XBP1, PERK-ATF4, and ATF6 pathways, in M98K-OPTN expressing cells. Splicing of XBP1, and ATF6 activation were higher in tunicamycin-treated M98K-OPTN expressing cells. Increased levels of PERK and IRE1α proteins in M98K-OPTN expressing cells were dependent on autophagy. Overall, our results show that M98K-OPTN sensitizes retinal cells to TNFα and ER stress-induced cell death. We also show that M98K-OPTN alters ER stress response signalling, which possibly enhances the sensitivity of retinal cells to ER stress. Our results provide support to the hypothesis that M98K-OPTN may cooperate with other genetic or environmental factors to cause retinal ganglion cell death associated with glaucoma.

Keywords:  ER stress; Glaucoma; Optineurin; RGC death; tumor necrosis factor α

DOI:  https://doi.org/10.1111/febs.16739
Curr Res Neurobiol. 2022 ;3 100037

Degeneration of retina-brain components and connections in glaucoma: Disease causation and treatment options for eyesight preservation.

Najam A Sharif.

  Eyesight is the most important of our sensory systems for optimal daily activities and overall survival. Patients who experience visual impairment due to elevated intraocular pressure (IOP) are often those afflicted with primary open-angle glaucoma (POAG) which slowly robs them of their vision unless treatment is administered soon after diagnosis. The hallmark features of POAG and other forms of glaucoma are damaged optic nerve, retinal ganglion cell (RGC) loss and atrophied RGC axons connecting to various brain regions associated with receipt of visual input from the eyes and eventual decoding and perception of images in the visual cortex. Even though increased IOP is the major risk factor for POAG, the disease is caused by many injurious chemicals and events that progress slowly within all components of the eye-brain visual axis. Lowering of IOP mitigates the damage to some extent with existing drugs, surgical and device implantation therapeutic interventions. However, since multifactorial degenerative processes occur during aging and with glaucomatous optic neuropathy, different forms of neuroprotective, nutraceutical and electroceutical regenerative and revitalizing agents and processes are being considered to combat these eye-brain disorders. These aspects form the basis of this short review article.

Keywords:  Axonal injury; Glaucoma; Intraocular pressure; Neurodegeneration; Neuroprotection; Optic nerve; Retina; Retinal ganglion cell

DOI:  https://doi.org/10.1016/j.crneur.2022.100037
Acta Neuropathol Commun. 2023 Jan 22. 11(1): 18

NAD salvage pathway machinery expression in normal and glaucomatous retina and optic nerve.

James R Tribble, Anna Hagström, Kenza Jusseaume, Emma Lardner, Raymond Ching-Bong Wong, Gustav Stålhammar, Pete A Williams.

  Glaucoma is the leading cause of irreversible blindness and is a major health and economic burden. Current treatments do not address the neurodegenerative component of glaucoma. In animal models of glaucoma, the capacity to maintain retinal nicotinamide adenine dinucleotide (NAD) pools declines early during disease pathogenesis. Treatment with nicotinamide, an NAD precursor through the NAD salvage pathway, robustly protects against neurodegeneration in a number of glaucoma models and improves vision in existing glaucoma patients. However, it remains unknown in humans what retinal cell types are able to process nicotinamide to NAD and how these are affected in glaucoma. To address this, we utilized publicly available RNA-sequencing data (bulk, single cell, and single nucleus) and antibody labelling in highly preserved enucleated human eyes to identify expression of NAD synthesizing enzyme machinery. This identifies that the neural retina favors expression of the NAD salvage pathway, and that retinal ganglion cells are particularly enriched for these enzymes. NMNAT2, a key terminal enzyme in the salvage pathway, is predominantly expressed in retinal ganglion cell relevant layers of the retina and declines in glaucoma. These findings suggest that human retinal ganglion cells can directly utilize nicotinamide and could maintain a capacity to do so in glaucoma, showing promise for ongoing clinical trials.

Keywords:  Axon degeneration; Glaucoma; Metabolism; NAD; Neurodegeneration; Nicotinamide; Optic nerve; Retinal ganglion cell

DOI:  https://doi.org/10.1186/s40478-023-01513-0
Front Endocrinol (Lausanne). 2022 ;13 1047642

Autophagy and senescence of rat retinal precursor cells under high glucose.

Hanhan Peng, Wentao Han, Benteng Ma, Shirui Dai, Jianfeng Long, Shu Zhou, Haoyu Li, Baihua Chen.

  Backgrounds: Diabetic retinopathy (DR) is a common diabetic ocular disease characterized by retinal ganglion cell (RGC) changes. An abnormal environment, hyperglycemia, may progressively alter the structure and function of RGCs, which is a primary pathological feature of retinal neurodegeneration in DR. Accumulated studies confirmed autophagy and senescence play a vital role in DR; however, the underlying mechanisms need to be clarified.Methods: This study included the microarray expression profiling dataset GSE60436 from Gene Expression Omnibus (GEO) to conduct the bioinformatics analysis. The R software was used to identify autophagy-related genes (ARGs) that were differentially expressed in fibrovascular membranes (FVMs) and normal retinas. Co-expression and tissue-specific expression were elicited for the filtered genes. The genes were then analyzed by ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Set Enrichment Analysis (GSEA). R28 cells were cultured with high glucose, detected by reverse transcription-quantitative (RT-qPCR) and stained by apoptosis kit.
Results: In the retina, 31 differentially expressed ARGs (24 up-regulated genes) were discovered and enriched. The enrichment results revealed that differentially expressed ARGs were significantly enriched in autophagy, apoptosis, aging, and neural function. Four hub genes (i.e., TP53, CASP1, CCL2, and CASP1) were significantly up-regulated. Upregulation of cellular autophagy and apoptosis level was detected in the hyperglycemia model in vitro.
Conclusions: Our results provide evidence for the autophagy and cellular senescence mechanisms involved in retinal hyperglycemia injury, and the protective function of autophagy is limited. Further study may favour understanding the disease progression and neuroprotection of DR.

Keywords:  apoptosis; autophagy; cellular senescence; computational biology; diabetic retinopathy (DR); differentially expressed genes

DOI:  https://doi.org/10.3389/fendo.2022.1047642