bims-mideyd 2023-07-16 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2023–07–16
eight papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Regulation of ABCA1 by miR-33 and miR-34a in the Aging Eye.
ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway.
Spermidine Attenuates High Glucose-Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Inhibiting Production of ROS and NF-κB/NLRP3 Inflammasome Pathway.
Endogenous and Exogenous Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells: An Updated Antioxidant Perspective.
Gene Expression of Clusterin, Tissue Inhibitor of Metalloproteinase-1, and Their Receptors in Retinal Pigment Epithelial Cells and Müller Glial Cells Is Modulated by Inflammatory Stresses.
Polarized RPE Secretome Preserves Photoreceptors in Retinal Dystrophic RCS Rats.
Oxidative Stress and Cellular Protein Accumulation Are Present in Keratoconus, Macular Corneal Dystrophy, and Fuchs Endothelial Corneal Dystrophy.
Role of TFEB in Diseases Associated with Lysosomal Dysfunction.

Adv Exp Med Biol. 2023 ;1415 55-59

Regulation of ABCA1 by miR-33 and miR-34a in the Aging Eye.

Florian Peters, Christian Grimm.

  Many age-related diseases, including age-related macular degeneration (AMD), go along with local lipid accumulation and dysregulated lipid metabolism. Several genes involved in lipid metabolism, including ATP-binding cassette transporter A1 (ABCA1), were associated with AMD through genome-wide association studies. Recent studies have shown that loss of ABCA1 in the retinal pigment epithelium (RPE) leads to lipid accumulation and RPE atrophy, a hallmark of AMD, and that antagonizing ABCA1-targeting microRNAs (miRNAs) attenuated pathological changes to the RPE or to macrophages. Here, we focus on two lipid metabolism-modulating miRNAs, miR-33 and miR-34a, which show increased expression in aging RPE cells, and on their potential to regulate ABCA1 levels, cholesterol efflux, and lipid accumulation in AMD pathogenesis.

Keywords:  ABCA1; AMD; Cholesterol; HDL; LXR; Lipid accumulation; Lipids; RPE; Reverse cholesterol transport; miRNA

DOI:  https://doi.org/10.1007/978-3-031-27681-1_9
Cell Rep. 2023 Jul 11. pii: S2211-1247(23)00790-8. [Epub ahead of print]42(7): 112779

ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway.

Ru-Xu Sun, Hong-Jing Zhu, Ye-Ran Zhang, Jia-Nan Wang, Ying Wang, Qiu-Chen Cao, Jiang-Dong Ji, Chao Jiang, Song-Tao Yuan, Xue Chen, Qing-Huai Liu.

  Retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV) are predominant features of age-related macular degeneration (AMD), with an unclear mechanism. Herein, we show that RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) is up-regulated in AMD. In RPE cells, ALKBH5 overexpression associates with depolarization, oxidative stress, disturbed autophagy, irregular lipid homeostasis, and elevated VEGF-A secretion, which subsequently promotes proliferation, migration, and tube formation of vascular endothelial cells. Consistently, ALKBH5 overexpression in mice RPE correlates with various pathological phenotypes, including visual impairments, RPE anomalies, choroidal neovascularization (CNV), and interrupted retinal homeostasis. Mechanistically, ALKBH5 regulates retinal features through its demethylation activity. It targets PIK3C2B and regulates the AKT/mTOR signaling pathway with YTHDF2 as the N6-methyladenosine reader. IOX1, an ALKBH5 inhibitor, suppresses hypoxia-induced RPE dysfunction and CNV progression. Collectively, we demonstrate that ALKBH5 induces RPE dysfunction and CNV progression in AMD via PIK3C2B-mediated activation of the AKT/mTOR pathway. Pharmacological inhibitors of ALKBH5, like IOX1, are promising therapeutic options for AMD.

Keywords:  ALKBH5; CP: Cell biology; IOX1; N(6)-methyladenosine; age-related macular degeneration; choroidal neovascularization; retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.celrep.2023.112779
Int J Mol Sci. 2023 Jun 23. pii: 10550. [Epub ahead of print]24(13):

Spermidine Attenuates High Glucose-Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Inhibiting Production of ROS and NF-κB/NLRP3 Inflammasome Pathway.

EunJin Bang, Cheol Park, Hyun Hwangbo, Jung-Hyun Shim, Sun-Hee Leem, Jin Won Hyun, Gi-Young Kim, Yung Hyun Choi.

  Diabetic retinopathy (DR) is the leading cause of vision loss and a critical complication of diabetes with a very complex etiology. The build-up of reactive oxygen species (ROS) due to hyperglycemia is recognized as a primary risk factor for DR. Although spermidine, a naturally occurring polyamine, has been reported to have antioxidant effects, its effectiveness in DR has not yet been examined. Therefore, in this study, we investigated whether spermidine could inhibit high glucose (HG)-promoted oxidative stress in human retinal pigment epithelial (RPE) cells. The results demonstrated that spermidine notably attenuated cytotoxicity and apoptosis in HG-treated RPE ARPE-19 cells, which was related to the inhibition of mitochondrial ROS production. Under HG conditions, interleukin (IL)-1β and IL-18's release levels were markedly increased, coupled with nuclear factor kappa B (NF-κB) signaling activation. However, spermidine counteracted the HG-induced effects. Moreover, the expression of nucleotide-binding oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome multiprotein complex molecules, including TXNIP, NLRP3, ASC, and caspase-1, increased in hyperglycemic ARPE-19 cells, but spermidine reversed these molecular changes. Collectively, our findings demonstrate that spermidine can protect RPE cells from HG-caused injury by reducing ROS and NF-κB/NLRP3 inflammasome pathway activation, indicating that spermidine could be a potential therapeutic compound for DR treatment.

Keywords:  NF-κB; NLRP3 inflammasome; ROS; apoptosis; spermidine

DOI:  https://doi.org/10.3390/ijms241310550
Int J Mol Sci. 2023 Jun 28. pii: 10776. [Epub ahead of print]24(13):

Endogenous and Exogenous Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells: An Updated Antioxidant Perspective.

Yuliya Markitantova, Vladimir Simirskii.

  The retinal pigment epithelium (RPE) performs a range of necessary functions within the neural layers of the retina and helps ensure vision. The regulation of pro-oxidative and antioxidant processes is the basis for maintaining RPE homeostasis and preventing retinal degenerative processes. Long-term stable changes in the redox balance under the influence of endogenous or exogenous factors can lead to oxidative stress (OS) and the development of a number of retinal pathologies associated with RPE dysfunction, and can eventually lead to vision loss. Reparative autophagy, ubiquitin-proteasome utilization, the repair of damaged proteins, and the maintenance of their conformational structure are important interrelated mechanisms of the endogenous defense system that protects against oxidative damage. Antioxidant protection of RPE cells is realized as a result of the activity of specific transcription factors, a large group of enzymes, chaperone proteins, etc., which form many signaling pathways in the RPE and the retina. Here, we discuss the role of the key components of the antioxidant defense system (ADS) in the cellular response of the RPE against OS. Understanding the role and interactions of OS mediators and the components of the ADS contributes to the formation of ideas about the subtle mechanisms in the regulation of RPE cellular functions and prospects for experimental approaches to restore RPE functions.

Keywords:  antioxidant therapy; endogenous cell defense; oxidative stress; reactive oxygen species; redox homeostasis; redox-sensitive transcription factors; retinal pigment epithelium; target genes

DOI:  https://doi.org/10.3390/ijms241310776
Adv Exp Med Biol. 2023 ;1415 215-219

Gene Expression of Clusterin, Tissue Inhibitor of Metalloproteinase-1, and Their Receptors in Retinal Pigment Epithelial Cells and Müller Glial Cells Is Modulated by Inflammatory Stresses.

Mengmei Zheng, Eun-Jin Lee, Shinwu Jeong, Cheryl Mae Craft.

  Balanced activities of matrix metalloproteinases (MMPs) and their inhibitors are essential for photoreceptor (PR) cell survival. PR rod cell survival in rodent models of inherited retinitis pigmentosa (RP) is prolonged by recombinant tissue inhibitor of metalloproteinase (TIMP)-1 or clusterin (CLU) proteins. Retinal pigment epithelial cells (RPE) and Müller glia (MG) cells support PR cells. In human RPE and MG cell lines, we measured their mRNA levels of the two genes with quantitative real-time PCR (qRT-PCR) with interleukin (IL)-1β treatment, a key pathological component in retinal degeneration. Endogenous CLU gene expression was significantly downregulated by IL-1β in both cell types, whereas TIMP-1 expression was upregulated in MG cells, suggesting the transcriptional control of CLU is potentially more sensitive to inflammatory conditions. The expression levels of CLU endocytic receptors revealed that the low-density lipoprotein receptor-related protein 2 (LRP2) was upregulated only in MG cells by the treatment with no detectable change in RPE cells. Like LRP2, IL-1β upregulated TIMP-1 receptor LRP1 expression in MG cells; however, it was decreased in the expression of RPE cells. These data suggest that the gene expression of CLU and TIMP-1 and their receptors may be dynamically modulated in inflammatory conditions.

Keywords:  Clusterin; Cytokine; Matrix metalloproteinase; Oxidative stress; Retinal degeneration; Tissue inhibitor of metalloproteinase 1

DOI:  https://doi.org/10.1007/978-3-031-27681-1_31
Cells. 2023 Jun 22. pii: 1689. [Epub ahead of print]12(13):

Polarized RPE Secretome Preserves Photoreceptors in Retinal Dystrophic RCS Rats.

Kabir Ahluwalia, Juan-Carlos Martinez-Camarillo, Biju B Thomas, Aditya Naik, Alejandra Gonzalez-Calle, Dimitrios Pollalis, Jane Lebkowski, Sun Young Lee, Debbie Mitra, Stan G Louie, Mark S Humayun.

  Retinal degenerative diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa, lack effective therapies. Conventional monotherapeutic approaches fail to target the multiple affected pathways in retinal degeneration. However, the retinal pigment epithelium (RPE) secretes several neurotrophic factors addressing diverse cellular pathways, potentially preserving photoreceptors. This study explored human embryonic stem cell-derived, polarized RPE soluble factors (PRPE-SF) as a combination treatment for retinal degeneration. PRPE-SF promoted retinal progenitor cell survival, reduced oxidative stress in ARPE-19 cells, and demonstrated critical antioxidant and anti-inflammatory effects for preventing retinal degeneration in the Royal College of Surgeons (RCS) rat model. Importantly, PRPE-SF treatment preserved retinal structure and scotopic b-wave amplitudes, suggesting therapeutic potential for delaying retinal degeneration. PRPE-SF is uniquely produced using biomimetic membranes for RPE polarization and maturation, promoting a protective RPE secretome phenotype. Additionally, PRPE-SF is produced without animal serum to avoid immunogenicity in future clinical development. Lastly, PRPE-SF is a combination of neurotrophic factors, potentially ameliorating multiple dysfunctions in retinal degenerations. In conclusion, PRPE-SF offers a promising therapeutic candidate for retinal degenerative diseases, advancing the development of effective therapeutic strategies for these debilitating conditions.

Keywords:  Royal College of Surgeons rat; age-related macular degeneration; photoreceptor; retina; retinal degeneration; retinal pigmented epithelium; retinitis pigmentosa; secretome

DOI:  https://doi.org/10.3390/cells12131689
J Clin Med. 2023 Jun 28. pii: 4332. [Epub ahead of print]12(13):

Oxidative Stress and Cellular Protein Accumulation Are Present in Keratoconus, Macular Corneal Dystrophy, and Fuchs Endothelial Corneal Dystrophy.

Linda Vottonen, Ali Koskela, Szabolcs Felszeghy, Adam Wylegala, Katarzyna Kryszan, Iswariyaraja Sridevi Gurubaran, Kai Kaarniranta, Edward Wylegala.

  The aim of the study was to investigate oxidative stress as well as cellular protein accumulation in corneal diseases including keratoconus (KC), macular corneal dystrophy (MCD), and Fuchs endothelial corneal dystrophy (FECD) at their primary affecting sites. Corneal buttons from KC, MCD, and FECD patients, as well as healthy controls, were analyzed immunohistochemically to evaluate the presence of oxidative stress and the function of the proteostasis network. 4-Fydroxynonenal (4-HNE) was used as a marker of oxidative stress, whereas the levels of catalase and heat-shock protein 70 (HSP70) were analyzed to evaluate the response of the antioxidant defense system and molecular chaperones, respectively. Sequestosome 1 (SQSTM1) levels were determined to assess protein aggregation and the functionality of autophagic degradation. Basal epithelial cells of the KC samples showed increased levels of oxidative stress marker 4-HNE and antioxidant enzyme catalase together with elevated levels of HSP70 and accumulation of SQSTM1. Corneal stromal cells and endothelial cells from MCD and FECD samples, respectively, showed similarly increased levels of these markers. All corneal diseases showed the presence of oxidative stress and activation of the molecular chaperone response to sustain protein homeostasis. However, the accumulation of protein aggregates suggests insufficient function of the protective mechanisms to limit the oxidative damage and removal of protein aggregates via autophagy. These results suggest that oxidative stress has a role in KC, MCD, and FECD at the cellular level as a secondary outcome. Thus, antioxidant- and autophagy-targeted therapies could be included as supporting care when treating KC or corneal dystrophies.

Keywords:  Fuchs endothelial corneal dystrophy; autophagy; keratoconus; macular corneal dystrophy; molecular chaperones; oxidative stress

DOI:  https://doi.org/10.3390/jcm12134332
Adv Exp Med Biol. 2023 ;1415 319-325

Role of TFEB in Diseases Associated with Lysosomal Dysfunction.

Hsuan-Yeh Pan, Mallika Valapala.

  Transcription factor EB (TFEB) plays a very important role in the maintenance of cellular homeostasis. TFEB is a transcription factor that regulates the expression of several genes in the Coordinated Lysosomal Expression and Regulation (CLEAR) network. The CLEAR network genes are known to regulate many processes associated with the autophagy pathway and lysosome biogenesis. Lysosomes, which are degradative organelles in the cell, are associated with several cellular mechanisms, such as autophagy and phagocytosis. Recent studies have shown that TFEB dysregulation and lysosomal dysfunction are associated with several degenerative diseases. Thus, enhancing TFEB activity and accompanied induction of lysosomal function and autophagy can have tremendous therapeutic potential for the treatment of several degenerative diseases including age-related macular degeneration (AMD). In this chapter, we briefly illustrate the expression and regulation of TFEB in response to several cellular stressors and discuss the effects of TFEB overexpression to induce cellular clearance functions.

Keywords:  Age-related macular degeneration (AMD); Lysosomal dysfunction; Neurodegeneration; Reactive oxygen species (ROS); Retinal pigment epithelium (RPE); Transcription factor EB (TFEB)

DOI:  https://doi.org/10.1007/978-3-031-27681-1_46