bims-mideyd 2022-01-02 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022–01–02
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Oxidative stress induces Z-DNA binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.
Differential effects of experimental glaucoma on intrinsically photosensitive retinal ganglion cells in mice.
Downregulation of AlphaB-crystallin in Retinal Pigment Epithelial Cells Exposed to Diabetes-related Stimuli In Vivo and In Vitro.
GPCR Signaling and mTORC1 Regulation.
Drp1 knockdown represses apoptosis of rat retinal endothelial cells by inhibiting mitophagy.
Melatonin counteracts oxidative damage in lens by regulation of Nrf2 and NLRP3 inflammasome activity.
Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life.

J Biol Chem. 2021 Dec 22. pii: S0021-9258(21)01333-8. [Epub ahead of print] 101523

Oxidative stress induces Z-DNA binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.

Jamal Saada, Ryan J McAuley, Michela Marcatti, Tony Zifeng Tang, Massoud Motamedi, Bartosz Szczesny.

  Oxidative stress, inflammation, and aberrant activation of microglia in the retina are commonly observed in ocular pathologies. In glaucoma or age-related macular degeneration, the chronic activation of microglia affects retinal ganglion cells and photoreceptors, respectively, contributing to gradual vision loss. However, the molecular mechanisms that cause activation of microglia in the retina are not fully understood. Here we show that exposure of retinal pigment epithelial (RPE) cells to chronic low-level oxidative stress induces mitochondrial DNA (mtDNA)-specific damage, and the subsequent translocation of damaged mtDNA to the cytoplasm results in the binding and activation of intracellular DNA receptor Z-DNA binding protein 1 (ZBP1). Activation of the mtDNA/ZBP1 pathway triggers the expression of pro-inflammatory markers in RPE cells. In addition, we show the enhanced release of extracellular vesicles (EVs) containing fragments of mtDNA derived from the apical site of RPE cells induces a pro-inflammatory phenotype of microglia via activation of ZBP1 signaling. Collectively, our report establishes oxidatively damaged mtDNA as an important signaling molecule with ZBP1 as its intracellular receptor in the development of an inflammatory response in the retina. We propose that this novel mtDNA-mediated autocrine and paracrine mechanism for triggering and maintaining inflammation in the retina may play an important role in ocular pathologies. Therefore, the molecular mechanisms identified in this report are potentially suitable therapeutic targets to ameliorate development of ocular pathologies.

Keywords:  extracellular vesicles; microglia; mitochondrial DNA; oxidative stress; retinal pigment epithelial

DOI:  https://doi.org/10.1016/j.jbc.2021.101523
J Comp Neurol. 2021 Dec 27.

Differential effects of experimental glaucoma on intrinsically photosensitive retinal ganglion cells in mice.

Jingyi Gao, Erin M Griner, Mingna Liu, Joanna Moy, Ignacio Provencio, Xiaorong Liu.

  Glaucoma is a group of eye diseases characterized by retinal ganglion cell (RGC) loss and optic nerve damage. Studies, including this study, support that RGCs degenerate and die in a type-specific manner following the disease insult. Here we specifically examined one RGC type, the intrinsically photosensitive retinal ganglion cell (ipRGC), and its associated functional deficits in a mouse model of experimental glaucoma. We induced chronic ocular hypertension (OHT) by laser photocoagulation and then characterized the survival of ipRGC subtypes. We found that ipRGCs suffer significant loss, similar to the general RGC population, but ipRGC subtypes are differentially affected following chronic OHT. M4 ipRGCs, which are involved in pattern vision, are susceptible to chronic OHT. Correspondingly, mice with chronic OHT experience reduced contrast sensitivity and visual acuity. By contrast, M1 ipRGCs, which project to the suprachiasmatic nuclei (SCN) to regulate circadian rhythmicity, exhibit almost no cell loss following chronic OHT. Accordingly, we observed that circadian re-entrainment and circadian rhythmicity are largely not disrupted in OHT mice. Our study demonstrates the link between subtype-specific ipRGC survival and behavioral deficits in glaucomatous mice. These findings provide insight into glaucoma-induced visual behavioral deficits and their underlying mechanisms. This article is protected by copyright. All rights reserved.

Keywords:  circadian rhythm; glaucoma; intrinsically photosensitive retinal ganglion cells (ipRGCs); melanopsin; ocular hypertension; visual acuity

DOI:  https://doi.org/10.1002/cne.25293
In Vivo. 2022 Jan-Feb;36(1):36(1): 132-139

Downregulation of AlphaB-crystallin in Retinal Pigment Epithelial Cells Exposed to Diabetes-related Stimuli In Vivo and In Vitro.

D I Wu, Satoru Kase, Y E Liu, Atsuhiro Kanda, Miyuki Murata, Susumu Ishida.

   BACKGROUND/AIM: AlphaB-crystallin plays a pivotal role in many diseases. However, the involvement of alphaB-crystallin in retinal pigment epithelial (RPE) cells with diabetes stimuli remains unknown. The aim of this study is to examine the alterations of RPE cells and alphaB-crystallin expression in diabetic models in vivo and in vitro.
MATERIALS AND METHODS: Diabetic conditions in mice were induced by streptozotocin (STZ). The thickness of the RPE/choroid complex was measured by optical coherence tomography (OCT). Periodic acid-Schiff (PAS) staining was used to investigate the choriocapillaris in histological sections of murine eyeballs and oxidative stress was evaluated using immunofluorescence with anti-4-hydroxynonenal (HNE) antibody. AlphaB-crystallin expression was examined in the RPE/choroid complex using ELISA. Real-Time PCR was performed to evaluate the alphaB-crystallin expression in cultured human RPE cells with high glucose or following advanced glycation end-products (AGE) stimulation.
RESULTS: In diabetic mice, OCT-based RPE/choroidal layers were thickened 2 months after STZ stimulation, where PAS-positive dilated choriocapillaris was noted. Immunoreactivity of 4-HNE was strongly observed in the RPE layer, from which a significant number of RPE cells was lost. Meanwhile, alphaB-crystallin expression in 2-month STZ mice was significantly lower compared to controls. In accordance with these results, in vitro data showed that the alphaB-crystallin expression was also significantly lower in RPE cells with high glucose or following AGE stimulation compared to untreated cells.
CONCLUSION: In both types of diabetic models the expression of alphaB-crystallin was found to be downregulated in RPE cells and was associated with increased levels of oxidative stress.

Keywords:  AlphaB-crystallin; advanced glycation end-products; high glucose; oxidative stress; retinal pigment epithelial cells; streptozotocin

DOI:  https://doi.org/10.21873/invivo.12684
Mol Pharmacol. 2021 Dec 28. pii: MOLPHARM-MR-2021-000302. [Epub ahead of print]

GPCR Signaling and mTORC1 Regulation.

Chase H Melick, Tshering D Lama-Sherpa, Adna Curukovic, Jenna L Jewell.

  The mammalian target of rapamycin (mTOR) senses upstream stimuli to regulate numerous cellular functions such as metabolism, growth, and autophagy. The activation of mTOR complex 1 (mTORC1) is typically observed in human disease and continues to be an important therapeutic target. Understanding the upstream regulators of mTORC1 will provide a crucial link to targeting mTORC1 hyperactivated diseases. In this review, we will discuss the regulation of mTORC1 by upstream stimuli, with a specific focus on G-protein coupled receptor (GPCR) signaling to mTORC1. Significance Statement mTORC1 is a master regulator of many cellular processes and is often hyperactivated in human disease. Therefore, understanding the molecular underpinnings of these pathways will undoubtedly be promising to the mTORC1 field and human disease.

Keywords:  G protein coupled signaling; G proteins; Mammalian target of rapamycin (mTOR); Protein Kinase A (PKA); g protein-coupled receptors (GPCRS)

DOI:  https://doi.org/10.1124/molpharm.121.000302
Acta Histochem. 2021 Dec 24. pii: S0065-1281(21)00159-8. [Epub ahead of print]124(1): 151837

Drp1 knockdown represses apoptosis of rat retinal endothelial cells by inhibiting mitophagy.

Hongxi Wu, Guodong Li, Weiwei Chen, Wenbin Luo, Zhongyi Yang, Zhipeng You, Yuling Zou.

  Diabetic retinopathy (DR) is the leading clinical cause of blindness in diabetic patients. Mitophagy participates in the pathogenesis of DR. Dynamin related protein 1 (Drp1) is associated with mitophagy. Here, we investigated whether Drp1 can regulate mitophagy to affect the progression of DR. We constructed DR rat model by administration of streptozocin. Primary rat retinal endothelial cells (RECs) were treated with high glucose (HG) as a DR cell model. Drp1 was highly expressed in the retinal tissues of DR rats and HG-treated RECs. Drp1 knockdown inhibited HG-mediated increase of reactive oxygen species (ROS) levels and apoptosis in RECs. Moreover, Drp1 silencing inhibited the expression of autophagy-related proteins LC3-II/LC3-1 and Beclin-1 and reduced LC3 puncta in HG-treated RECs. The expression of mitochondrial marker Tom20 was reduced and the levels of mitophagy were increased in the HG-treated RECs, which was rescued by Drp1 silencing. Drp1 knockdown repressed LC3-II expression in HG-treated RECs, indicating that autophagy flux was inhibited. Rapamycin (autophagy activator) enhanced ROS levels and apoptosis in HG-treated RECs by activating autophagy, which was rescued by Drp1 knockdown. In conclusion, these data demonstrated that Drp1 knockdown repressed apoptosis of rat retinal endothelial cells by inhibiting mitophagy. Thus, this work suggests that targeted regulation of Drp1 may become a treatment for DR.

Keywords:  Apoptosis; Diabetic retinopathy; Drp1; Rat retinal endothelial cells

DOI:  https://doi.org/10.1016/j.acthis.2021.151837
Exp Eye Res. 2021 Dec 26. pii: S0014-4835(21)00478-4. [Epub ahead of print] 108912

Melatonin counteracts oxidative damage in lens by regulation of Nrf2 and NLRP3 inflammasome activity.

Victoria Eugenia Lledó, Hanan Award Alkozi, Juan Sánchez-Naves, Miguel Angel Fernandez-Torres, Ana Guzman-Aranguez.

  Oxidative stress, generated because of an imbalance between reactive oxygen species (ROS) generation and elimination, is associated with lens damage and cataract progression. ROS generation is known to activate NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-cointaining 3) inflammasome, and is believed to be an important link between oxidative stress and inflammation, that is also related to cataract development. Potential oxidative hazard to the lens by white light-emitting diode (LED) light, a source of illumination commonly used nowadays, has been suggested, although available information is limited. In this work, we evaluated the cytotoxicity induced by hydrogen peroxide (an oxidative stressor agent) and white LED light in lens epithelial cells as well as melatonin ability to counteract the effects induced by them. Melatonin is a neurohormone secreted by different ocular structures that could be useful to alleviate oxidative damage induced by different oxidative stressors in lens. Particularly, the modulation of Nrf2 (nuclear erythroid 2-related factor)/Keap 1 (Kelch-like ECH-associated protein 1), an essential oxidative stress regulator, and NLRP3 activity by melatonin was evaluated in lens epithelial cells. ROS levels rose after white LED light exposure and cell viability was reduced after challenge with oxidative stressor agents. Melatonin prevented cell death triggered by hydrogen peroxide and white LED light, precluded ROS generation induced by white LED light and promoted antioxidant lens capacity through upregulation of Nrf2 protein levels and SOD activity. NLRP3, caspase-1 and IL1-β expression significantly increased in human lens cells exposed to H2O2 or irradiated with white LED light. Activation of NLRP3 inflammasome triggered by oxidative stressors was also abrogated by melatonin. Attenuation of inflammatory and cytotoxic effects induced by oxidative stressors provided by melatonin in lens indicate the interest of this molecule as a potential therapeutic agent for cataract prevention/management.

Keywords:  Cataracts; Lens; Melatonin; NLRP3; Nrf2; Oxidative stress; White light-emitting diode light

DOI:  https://doi.org/10.1016/j.exer.2021.108912
Prog Retin Eye Res. 2021 Dec 28. pii: S1350-9462(21)00098-7. [Epub ahead of print] 101037

Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life.

Dominik Lewandowski, Christopher L Sander, Aleksander Tworak, Fangyuan Gao, Qianlan Xu, Dorota Skowronska-Krawczyk.

  The retinal pigment epithelium-photoreceptor interphase is renewed each day in a stunning display of cellular interdependence. While photoreceptors use photosensitive pigments to convert light into electrical signals, the RPE supports photoreceptors in their function by phagocytizing shed photoreceptor tips, regulating the blood retina barrier, and modulating inflammatory responses, as well as regenerating the 11-cis-retinal chromophore via the classical visual cycle. These processes involve multiple protein complexes, tightly regulated ligand-receptors interactions, and a plethora of lipids and protein-lipids interactions. The role of lipids in maintaining a healthy interplay between the RPE and photoreceptors has not been fully delineated. In recent years, novel technologies have resulted in major advancements in understanding several facets of this interplay, including the involvement of lipids in phagocytosis and phagolysosome function, nutrient recycling, and the metabolic dependence between the two cell types. In this review, we aim to integrate the complex role of lipids in photoreceptor and RPE function, emphasizing the dynamic exchange between the cells as well as discuss how these processes are affected in aging and retinal diseases.

Keywords:  Aging; Docosahexaenoic acid (DHA); Membranes; Phospholipids; Polyunsaturated fatty acid (PUFA); Retina; Rod outer segment

DOI:  https://doi.org/10.1016/j.preteyeres.2021.101037