bims-mideyd 2022-10-09 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022‒10‒09
eight papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Ginkgo biloba extracts (GBE) protect human RPE cells from t-BHP-induced oxidative stress and necrosis by activating the Nrf2-mediated antioxidant defence.
Oxidized low-density lipoprotein causes ribosome reduction and inhibition of protein synthesis in retinal pigment epithelial cells.
AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation.
New strategies for neuro protection in glaucoma.
The transcriptome profile of RPE cells by the fullerenol against hydrogen peroxide stress.
Effect of human umbilical cord mesenchymal stem cell exosomes on aerobic metabolism of human retinal pigment epithelial cells.
Accelerated aging phenotypes in the retinal pigment epithelium of Zmpste24-deficient mice.
Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy.

J Pharm Pharmacol. 2022 Oct 03. pii: rgac069. [Epub ahead of print]

Ginkgo biloba extracts (GBE) protect human RPE cells from t-BHP-induced oxidative stress and necrosis by activating the Nrf2-mediated antioxidant defence.

Yue Li, Xue Zhu, Ke Wang, Ling Zhu, Michael Murray, Fanfan Zhou.

  OBJECTIVES: Age-related macular degeneration (AMD) is a prevalent ocular disease. Dry AMD accounts for most cases of blindness associated with AMD but there are no treatments. Oxidative stress-induced damage to retinal pigment epithelial (RPE) cells is a major contributor to the pathogenesis of dry AMD. This study investigated the protective actions of Ginkgo biloba extracts (GBE) in human RPE cells subjected to tert-butyl hydroperoxide (t-BHP)-mediated oxidative stress.METHODS: The human ARPE-19 cells were pre-treated with or without GBE before the exposure to t-BHP. Cell viability, cell death profile and lipid peroxidation were assessed. The findings were verified using human primary RPE cultures.
KEY FINDINGS: GBE pre-treatment prevented the increase in lipid peroxidation and necrosis/ferroptosis, and the concurrent viability decrease in RPE cells exposed to t-BHP. It enabled the pronounced activation of Nrf2 and its downstream genes. We found that ERK1/2 phosphorylation was increased to a similar extent by t-BHP and GBE.
CONCLUSION: This study revealed that GBE pre-treatment attenuates pro-oxidant stress and protects human RPE cells from oxidative injury by modulating ERK1/2-Nrf2 axis. These findings suggest that GBE has the potential to be developed as a agent that may be valuable in decreasing AMD progression.

Keywords:   Ginkgo biloba extracts; Nrf2; age-related macular degeneration; anti-oxidation; ferroptosis; retinal pigment epithelium; signalling pathway

DOI:  https://doi.org/10.1093/jpp/rgac069
Biochem Biophys Rep. 2022 Dec;32 101345

Oxidized low-density lipoprotein causes ribosome reduction and inhibition of protein synthesis in retinal pigment epithelial cells.

Francesco Giorgianni, Sarka Beranova-Giorgianni.

  Retinal pigment epithelium (RPE) are specialized multifunctional cells indispensable for maintenance of vision. Dysfunction and death of the RPE cells is implicated in the genesis and progression of age-related macular degeneration (AMD). Oxidative stress and resulting cellular damage plays a critical mechanistic role in AMD pathogenesis. Oxidized low-density lipoprotein (oxLDL), derived from LDL in a pro-oxidative environment, is found adjacent to the RPE as part of drusen, extracellular deposits that are a characteristic clinical feature of AMD. OxLDL is cytotoxic and oxLDL-induced oxidative damage may contribute to functional impairment of the RPE. Therefore, knowledge of how the RPE respond to oxLDL exposure is important to understand the mechanisms underlying RPE dysfunction and death associated with AMD. The objective of this study was to characterize alterations in the RPE proteome triggered by exposure to non-cytotoxic levels of oxLDL. Protein identification and quantification were performed with a high -resolution LC-MS/MS-based proteomics workflow. In total, out of the ca 3000 RPE proteins quantified, oxLDL treatment caused expression changes of 303 proteins. As revealed by protein functional analysis, oxLDL uptake caused a multifaceted molecular response that involved numerous biological pathways. This response included up-regulation of anti-oxidative stress proteins whose expression is mediated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), confirming results of transcriptomics studies previously published by us and others. Significantly, and previously unreported, the oxLDL treatment induced down-regulation of ribosomal and translation initiation proteins, and up-regulation of proteins involved in autophagy, thus suggesting that a major cellular mechanism through which the RPE mitigate oxLDL-induced damage involves inhibition of protein synthesis and removal of misfolded proteins.

Keywords:  Drusen; Oxidative stress; Oxidized LDL; Proteome; Proteostasis; Retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.bbrep.2022.101345
BMB Rep. 2022 Oct 05. pii: 5694. [Epub ahead of print]

AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation.

Yujin Park, Yeeun Jeong, Sumin Son, Dong-Eun Kim.

The implications of nutrient starvation due to aging on the degeneration of the retinal pigment epithelium (RPE) is yet to be fully explored. We examined the involvement of AMPK activation in mitochondrial homeostasis and its relationship with the maintenance of a healthy mitochondrial population and epithelial characteristics of RPE cells under nutrient starvation. Nutrient starvation induced mitochondrial senescence, which led to the accumulation of reactive oxygen species (ROS) in RPE cells. As nutrient starvation persisted, RPE cells underwent pathological epithelial-mesenchymal transition (EMT) via the upregulation of TWIST1, a transcription regulator which is activated by ROS-induced NF-κB signaling. Enhanced activation of AMPK with metformin decelerated mitochondrial senescence and EMT progression through mitochondrial biogenesis, primed by activation of PGC1-α. Thus, by facilitating mitochondrial biogenesis, AMPK protects RPE cells from the loss of epithelial integrity due to the accumulation of ROS in senescent mitochondria under nutrient starvation.
Front Cell Dev Biol. 2022 ;10 983195

New strategies for neuro protection in glaucoma.

Yang Xuejiao, Yan Junwei.

  Glaucoma is a progressive, irreversible loss of retinal ganglion cells (RGCs) and axons that results in characteristic optic atrophy and corresponding progressive visual field defect. The exact mechanisms underlying glaucomatous neuron loss are not clear. The main risk factor for glaucoma onset and development is high intraocular pressure (IOP), however traditional IOP-lowering therapies are often not sufficient to prevent degeneration of RGCs and the vision loss may progress, indicating the need for complementary neuroprotective therapy. This review summarizes the progress for neuro protection in glaucoma in recent 5 years, including modulation of neuroinflammation, gene and cell therapy, dietary supplementation, and sustained-release system.

Keywords:  gene therapy; glaucoma; gliocyte; neuroprotection; retinal ganglion cells

DOI:  https://doi.org/10.3389/fcell.2022.983195
Front Med (Lausanne). 2022 ;9 996280

The transcriptome profile of RPE cells by the fullerenol against hydrogen peroxide stress.

Xiaojun Wu, Fuwen Yao, Jing-Ying Xu, Jiao Chen, Ying Lu, Wei Li, Jing Deng, Lisha Mou, Qingling Zhang, Zuihui Pu.

  Age-related macular degeneration (AMD) causes central vision impairment with increased incidence. In the pathogenesis of AMD, reactive oxygen species (ROS) are associated with RPE cell apoptosis. H2O2 is an oxidative toxicant and is used to establish the AMD in vitro model. However, the mechanisms of ROS in H2O2-induced AMD are still unclear. Fullerenol, a promising antioxidant of nanomaterials, protects RPE cells from ROS attack. In addition to working as a scavenger, little is known about the antioxidant mechanism of fullerenol in RPE cells. In this study, transcriptome sequencing was performed to examine the global changes in mRNA transcripts induced by H2O2 in human ARPE-19 cells. Moreover, we comprehensively investigated the protective effects of fullerenol against H2O2-induced oxidative injury by RNA sequencing. Gene Ontology enrichment analysis showed that those pathways related to the release of positive regulation of DNA-templated transcription and negative regulation of apoptotic process were affected. Finally, we found that 12 hub genes were related to the oxidative-protection function of fullerenol. In summary, H2O2 affected these hub genes and signaling pathways to regulate the senescence of RPE cells. Moreover, fullerenol is a potent nanomaterial that protects the RPE and would be a promising approach for AMD prevention.

Keywords:  AMD; RNA sequencing; RPE; fullerenol; nanomaterial; oxidative stress; senescence

DOI:  https://doi.org/10.3389/fmed.2022.996280
Int Ophthalmol. 2022 Oct 05.

Effect of human umbilical cord mesenchymal stem cell exosomes on aerobic metabolism of human retinal pigment epithelial cells.

Lian Liu, Chunlan Liang, Wei Fan, Jingxiang Zhong.

  PURPOSE: To investigate the effect of exosomes secreted by human umbilical cord mesenchymal stem cells (HUCMSC-Exo) on aerobic metabolism of cobalt chloride (CoCl2)-induced oxidative damage in the human retinal pigment epithelial cell line (ARPE-19), and to explore the protective mechanism of HUCMSC-Exo on oxidative damage in ARPE-19 cells.METHODS: HUCMSC-Exo were extracted and identified; CCK-8 assay was used to established the oxidative damage mode of ARPE-19 cells induced by CoCl2; JC-1 flow cytometry was used to detect the effects of exosomes with different concentrations (0, 25, 50, or 100 μg/mL) on the mitochondrial membrane potential (MMP) of oxidatively damaged ARPE-19 cells. The effects of exosomes with different concentrations on the activity of oxidative metabolic enzymes (oxidative respiratory chain complexes I, III, IV, and V) and ATP synthesis in oxidatively damaged ARPE-19 cells were detected by spectrophotometry.
RESULTS: Under transmission electron microscope, HUCMSC-Exo were round or oval membrane vesicles with diameters of about 40-100 nm. Western blot results showed that HUCMSC-Exo expressed specific marker proteins CD63 and CD81. CCK-8 dates showed that the cell viability of ARPE-19 cells was significantly decreased with increasing CoCl2 concentration, and the concentration of 400 μmol/L CoCl2 was chosen to be the optimal concentration for oxidative damage. MMP was increased in exosomes intervention group (25, 50 or 100 μg/mL), and the dates were statistically different from 0 μg/mL exosome intervention group (P < 0.05). The activities of mitochondrial complexes I, IV, and V in exosomes intervention groups (100 μg/mL) were higher than those in 0 μg/mL exosome intervention group. In 50 μg/mL and 100 μg/mL exosome intervention group, ATP synthesis was significantly different from the 0 μg/mL exosome intervention group (P < 0.05).
CONCLUSION: HUCMSC-Exo had a certain protective effect on ARPE-19 cells induced by CoCl2 in vitro. The protective mechanism of HUCMSC-Exo on oxidative damage ARPE-19 cells might be through saving its aerobic metabolic function, restoring cell ATP synthesis, and improving the ability of cells to repair damage and deal with the hypoxic environment.

Keywords:  ARPE-19 cells; ATP synthesis; Aerobic metabolism; HUCMSC exosomes; Oxidative damage; Respiratory chains complex enzyme activity

DOI:  https://doi.org/10.1007/s10792-022-02530-z
Biochem Biophys Res Commun. 2022 Sep 25. pii: S0006-291X(22)01317-1. [Epub ahead of print]632 62-68

Accelerated aging phenotypes in the retinal pigment epithelium of Zmpste24-deficient mice.

Jae-Byoung Chae, Chul-Woo Park, Hyeong Min Lee, Leo Sungwong Choi, Chaehee Park, Junghoon Kim, Jaejin Shin, Jooseung Hyeon, Jihan Lee, Hyungwoo Lee, Hyung Soon Park, Chang-Hoon Nam, Hyewon Chung.

  Age-related macular degeneration (AMD) is a chronic and progressive disease characterized by degeneration of the retinal pigment epithelium (RPE) and retina that ultimately leads to loss of vision. The pathological mechanisms of AMD are not fully known. Cellular senescence, which is a state of cell cycle arrest induced by DNA-damage or aging, is hypothesized to critically affect the pathogenesis of AMD. In this study, we examined the relationship between cellular senescence and RPE/retinal degeneration in mouse models of natural aging and accelerated aging. We performed a bulk RNA sequencing of the RPE cells from adult (8 months old) and naturally-aged old (24 months old) mice and found that common signatures of senescence and AMD pathology - inflammation, apoptosis, and blood vessel formation - are upregulated in the RPE of old mice. Next, we investigated markers of senescence and the degree of RPE/retinal degeneration in Zmpste24-deficient (Zmpste24-/-) mice, which is a model for progeria and accelerated aging. We found that Zmpste24-/- mice display markedly greater level of senescence-related markers in RPE and significant RPE/retinal degeneration compared to wild-type mice, in a manner consistent with natural aging. Overall, these results provide support for the association between cellular senescence of RPE and the pathogenesis of AMD, and suggest the use of Zmpste24-/- mice as a novel senescent RPE model of AMD.

Keywords:  AMD; RPE; Retina; Senescence; Zmpste24

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.061
Front Pharmacol. 2022 ;13 980742

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy.

Eden Dubchak, Gideon Obasanmi, Matthew R Zeglinski, David J Granville, Sonia N Yeung, Joanne A Matsubara.

  Age-related ocular diseases are the leading cause of blindness in developed countries and constitute a sizable socioeconomic burden worldwide. Age-related macular degeneration (AMD) and Fuchs endothelial corneal dystrophy (FECD) are some of the most common age-related diseases of the retina and cornea, respectively. AMD is characterized by a breakdown of the retinal pigment epithelial monolayer, which maintains retinal homeostasis, leading to retinal degeneration, while FECD is characterized by degeneration of the corneal endothelial monolayer, which maintains corneal hydration status, leading to corneal edema. Both AMD and FECD pathogenesis are characterized by disorganized local extracellular matrix (ECM) and toxic protein deposits, with both processes linked to aberrant protease activity. Granzyme B (GrB) is a serine protease traditionally known for immune-mediated initiation of apoptosis; however, it is now recognized that GrB is expressed by a variety of immune and non-immune cells and aberrant extracellular localization of GrB substantially contributes to various age-related pathologies through dysregulated cleavage of ECM, tight junction, and adherens junction proteins. Despite growing recognition of GrB involvement in multiple age-related pathologies, its role in AMD and FECD remains poorly understood. This review summarizes the pathophysiology of, and similarities between AMD and FECD, outlines the current knowledge of the role of GrB in AMD and FECD, as well as hypothesizes putative contributions of GrB to AMD and FECD pathogenesis and highlights the therapeutic potential of pharmacologically inhibiting GrB as an adjunctive treatment for AMD and FECD.

Keywords:  Bruch’s membrane; Descemet’s membrane; corneal endothelium; extracellular matrix; retinal pigment epithelium; serine protease

DOI:  https://doi.org/10.3389/fphar.2022.980742