bims-mideyd 2025-08-31 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2025–08–31
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

The Mechanism of PMC (2,2,5,7,8-Pentamethyl-6-chromanol), a Sterically Hindered Phenol Antioxidant, in Rescuing Oxidized Low-Density-Lipoprotein-Induced Cytotoxicity in Human Retinal Pigment Epithelial Cells.
PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy.
High-Resolution Imaging and Interpretation of Three-Dimensional RPE Sheet Structure.
SP1-activated CFL2 promotes high glucose-induced retinal pigment epithelial cell injury and involves the AMPK/mTOR pathway.
The intersection of mitochondria, lipids, and ferroptosis: a new avenue for dry age-related macular degeneration.
Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4.
The PERK-p38 MAPK Axis Drives Endoplasmic Reticulum Stress-Induced Apoptosis in Fuchs Endothelial Corneal Dystrophy.

Antioxidants (Basel). 2025 Aug 14. pii: 996. [Epub ahead of print]14(8):

The Mechanism of PMC (2,2,5,7,8-Pentamethyl-6-chromanol), a Sterically Hindered Phenol Antioxidant, in Rescuing Oxidized Low-Density-Lipoprotein-Induced Cytotoxicity in Human Retinal Pigment Epithelial Cells.

Suman Chaudhary, Jean Moon, Zhengping Hu, Emil Kriukov, Sergio Pestun, Petr Y Baranov, Yin-Shan Eric Ng, Patricia A D'Amore.

  Geographic atrophy or late-stage dry age-related macular degeneration (AMD) is characterized by drusen deposition and progressive retinal pigment epithelium (RPE) degeneration, leading to irreversible vision loss. The formation of drusen leads to dyshomeostasis, oxidative stress, and irreversible damage to the RPE. In this study, we used an in vitro model of oxidized low-density lipoprotein (ox-LDL)-induced human RPE damage/death to investigate the mechanism through which a sterically hindered phenol antioxidant compound, PMC (2,2,5,7,8-pentamethyl-6-chromanol), protects the RPE against ox-LDL-induced damage. We show that PMC exerts its protective effect by preventing the upregulation of stress-responsive heme oxygenase-1 (HMOX1/HO-1) and NAD(P)H: quinone oxidoreductase (NQO1) at the mRNA and protein levels. This effect was due to PMC's blockade of ROS generation, which in turn blocked nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, ultimately preventing the upregulation of antioxidant response elements (AREs), including HMOX1 and NQO1. The key role of HO-1 was demonstrated when the protective effect of PMC was inhibited by the knockdown of HMOX1. Additionally, PMC treatment under different experimental conditions and at different time points revealed that the continuous presence of PMC is required for the optimal protection against ox-LDL-induced cytotoxicity, defining the cellular pharmacokinetics of this molecule. Our data demonstrate the involvement of a key antioxidant pathway through which PMC mitigates the oxidative stress induced by ox-LDL and provides a potential therapeutic strategy for suppressing RPE degeneration/damage during AMD progression.

Keywords:  antioxidants; cytoprotection; geographic atrophy; oxidized low-density lipoproteins; retinal pigment epithelium; sterically hindered phenols

DOI:  https://doi.org/10.3390/antiox14080996
Adv Sci (Weinh). 2025 Aug 25. e11288

PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy.

Jian Zhao, Junbiao Zhang, Yanli Liu, Lili Wang, Chunxi Huang, Wei Chi, Meixia An.

  Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, yet its pathogenesis remains incompletely understood. The retinal pigment epithelium (RPE) plays a vital role in maintaining retinal homeostasis. In this study, the expression of senescence marker protein p16 is observed to be upregulated in the RPE of early DR mouse models. Transcriptomic profiling reveals that PDZ domain protein 1 (PDZK1) expression is downregulated in RPE cells after 48 hours of high-glucose stimulation. Overexpression of PDZK1 reduces senescence markers in RPE cells, promoting cell proliferation and transport functions. Mechanistically, PDZK1 alleviates RPE cell senescence by interacting with 14-3-3ε to regulate the mTOR pathway, which is closely related to reducing oxidative stress and enhancing autophagy flux. In streptozotocin-induced DR mouse models, both PDZK1 overexpression-mediated senescence inhibition and Nutlin-3a-induced clearance of senescent RPE cells successfully downregulate retinal senescence markers and improve early-stage DR lesions. In summary, this study identifies a novel PDZK1-14-3-3ε-mTOR axis governing high-glucose-induced RPE cell senescence, and provides the first direct evidence linking RPE cell senescence to DR pathogenesis. These findings reveal a promising therapeutic strategy for DR intervention.

Keywords:  14‐3‐3ε; PDZK1; cell senescence; diabetic retinopathy; retinal pigment epithelium

DOI:  https://doi.org/10.1002/advs.202511288
Biomolecules. 2025 Jul 26. pii: 1084. [Epub ahead of print]15(8):

High-Resolution Imaging and Interpretation of Three-Dimensional RPE Sheet Structure.

Kevin J Donaldson, Micah A Chrenek, Jeffrey H Boatright, John M Nickerson.

  The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell-to-cell contact and barrier function, as well as conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers. We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (α-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misidentifying multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO3 oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes.

Keywords:  3D reconstruction; EMT; RPE; blood–retina barrier; cell segmentation; multinucleation; retinal pigment epithelium

DOI:  https://doi.org/10.3390/biom15081084
J Diabetes Investig. 2025 Aug 26.

SP1-activated CFL2 promotes high glucose-induced retinal pigment epithelial cell injury and involves the AMPK/mTOR pathway.

Jinan Xiao, Jingni Yu, Mei Ren.

   BACKGROUND: Cofilin-2 (CFL2) belongs to the cofilin family of actin-binding proteins and plays an important role in the actin homeostasis of muscle cells. CFL2 has been confirmed to regulate diabetic retinopathy (DR) progression. However, the current research is limited and more evidence is needed to reveal its role and mechanism in the DR process.
METHODS: Retinal pigment epithelial (RPE) cells (ARPE-19) were cultured in high-glucose (HG; 30 mM) conditions to mimic DR cell models. Cell proliferation and apoptosis were examined by CCK8 assay, EdU assay, flow cytometry, and caspase 3 activity detection. Cell oxidative stress, ferroptosis, and inflammation were evaluated by detecting ROS, MDA, SOD, GSH, Fe2+, TNF-α, and IL-1β levels. The mRNA and protein levels of CFL2 and special protein 1 (SP1) were tested by qRT-PCR and western blot. CFL2 and SP1 interaction was assessed by ChIP assay and dual-luciferase reporter assay.
RESULTS: HG suppressed ARPE-19 cell proliferation, while inducing apoptosis, oxidative stress, ferroptosis, and inflammation. Silencing of CFL2 alleviated HG-induced ARPE-19 cell injury by inhibiting cell apoptosis, oxidative stress, ferroptosis, and inflammation. SP1 could bind to CFL2 promoter regions to increase its expression. SP1 knockdown relieved HG-induced ARPE-19 cell injury via decreasing CFL2 expression. Besides, SP1 knockdown inhibited the activity of the AMPK/mTOR pathway, and CFL2 overexpression could reverse this effect.
CONCLUSIONS: CFL2, activated by SP1, promoted HG-induced RPE cell injury through regulating the AMPK/mTOR pathway, which might provide a potential target for DR.

Keywords:  CFL2; Diabetic retinopathy; Retinal pigment epithelial cells

DOI:  https://doi.org/10.1111/jdi.70144
Apoptosis. 2025 Aug 21.

The intersection of mitochondria, lipids, and ferroptosis: a new avenue for dry age-related macular degeneration.

Jacob Dohl, Gordon Burns, Mithalesh Singh.

  Age-related macular degeneration (AMD) is currently the leading cause of vision loss in developed countries. Despite decades of research and development, there are currently no treatments for the dry version of the illness. Dry AMD (DAMD) is a multifactorial disease stemming from dysfunction in the complement system, mitochondrial function, and lipid metabolism. While the complement system has been studied in-depth for its involvement in DAMD, mitochondria and lipids are understudied for their potential contributions to this process. Ferroptosis, an iron-dependent cell death mechanism, is associated with mitochondrial dysfunction and lipid dysregulation, and has been implicated as a driver of DAMD. This review describes the pathology of DAMD and the potential role of mitochondria, metabolism, and lipid dysregulation in the disease. We will highlight the intersection of pathways involving mitochondria, lipid dysregulation, and ferroptosis in DAMD progression, as well as the need for future studies to elucidate this connection.

Keywords:  Age-related macular degeneration; Ferroptosis; Lipids; Mitochondria; Reactive oxygen species; Retina

DOI:  https://doi.org/10.1007/s10495-025-02165-2
J Diabetes Res. 2025 ;2025 1924668

Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in Müller Cells of the Diabetic Neural Retina by Modulating ACSL4.

Xinlu Li, Bai Li, Defei Feng, Han Hu, Binyang Tang, Jingying Yang, Huaiyan Jiang, Li Li, Xiaojing Dong, Ninghua Ni, Yan Mei.

  Diabetic retinopathy (DR), a leading cause of vision impairment worldwide, is characterized by early neuronal damage in the retina, termed diabetic neuropathy in the retina (DNR). This condition is marked by neuronal apoptosis and glial activation. Müller glia are retinal cells highly susceptible to diabetic metabolic stress that may undergo ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, the role of ferroptosis in DNR pathogenesis remains undefined. In this study, we investigated Müller cell injury under high-glucose and palmitic acid (HGP) conditions. The retinal tissues were obtained from normal rabbits and alloxan-induced diabetic rabbits. HGP exposure significantly reduced Müller cell viability, induced cell cycle arrest, and elevated proinflammatory cytokines. Ultrastructural analysis revealed mitochondrial damage, accompanied by decreased glutathione (GSH) and increased malondialdehyde (MDA), ferrous iron (Fe2+), and reactive oxygen species (ROS) levels. RNA sequencing (RNA-Seq) identified SQSTM1 as a ferroptosis-related differentially expressed gene, which was significantly upregulated in HGP-treated cells. In vivo, DNR rabbits exhibited oxidative stress, iron dysregulation, and elevated SQSTM1 expression that colocalized with GFAP+ Müller cells. Single-cell RNA-Seq of human proliferative diabetic retinopathy (PDR) retinas confirmed elevated SQSTM1 expression in Müller cells compared to healthy control (HC) retinas. Mechanistically, SQSTM1 knockdown attenuated ferroptosis, oxidative stress, and HGP-induced injury, while its overexpression exacerbated ferroptosis via ACSL4 upregulation. Overall, our findings suggest that SQSTM1 may serve as a critical mediator linking Müller cell dysfunction and ferroptosis in DNR pathogenesis, offering a novel potential therapeutic target.

Keywords:  Müller cell; SQSTM1; diabetic neuropathy in retina (DNR); ferroptosis; oxidative stress

DOI:  https://doi.org/10.1155/jdr/1924668
Invest Ophthalmol Vis Sci. 2025 Aug 01. 66(11): 63

The PERK-p38 MAPK Axis Drives Endoplasmic Reticulum Stress-Induced Apoptosis in Fuchs Endothelial Corneal Dystrophy.

Takako Onishi, Taichi Yuasa, Naoyuki Ueda, Keita Miyadai, Theofilos Tourtas, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi, Naoki Okumura.

Purpose: To investigate the role of p38 mitogen-activated protein kinase (MAPK) in endoplasmic reticulum (ER) stress-induced corneal endothelial cell death in Fuchs endothelial corneal dystrophy (FECD) and to evaluate its potential as a therapeutic target.
Methods: Three complementary ER stress models were utilized: (1) FECD patient-derived (iFECD) cells treated with TGF-β to mimic disease-specific conditions, (2) normal immortalized human corneal endothelial cells (iHCECs) treated with thapsigargin, and (3) iHCECs treated with MG-132 (a proteasome inhibitor). The p38 MAPK activity was modulated using three structurally distinct p38 MAPK-specific inhibitors (SB203580, PH-797804, and VX-702). Gene-specific siRNA knockdown of protein kinase RNA-like ER kinase (PERK) pathway components was performed to elucidate the signaling hierarchy. PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-CCAAT/enhancer-binding protein homologous protein (CHOP) pathway activation, p38 MAPK phosphorylation, aggresome formation, mitochondrial function, and apoptosis were evaluated by western blotting, immunofluorescence, and flow cytometry.
Results: In all three models, p38 MAPK activation occurred downstream of PERK-eIF2α phosphorylation but upstream of ATF4-CHOP induction. In the iFECD/TGF-β model, p38 MAPK inhibition prevented CHOP upregulation, maintained mitochondrial membrane potential, and reduced apoptosis without affecting TGF-β-Smad signaling or aggresome formation. Similar protective effects were observed in iHCEC cells treated with thapsigargin or MG-132. Mechanistically, PERK knockdown prevented p38 MAPK activation, but p38 MAPK inhibition did not affect PERK activation, thereby establishing their hierarchical relationship.
Conclusions: p38 MAPK serves as a critical mediator of ER stress-induced apoptosis in corneal endothelial cells, where it functions as a molecular switch between adaptive and pro-apoptotic UPR signaling. The cytoprotective efficacy of p38 MAPK inhibitors across multiple ER stress models suggests their potential for therapeutic repurposing in FECD.

DOI: https://doi.org/10.1167/iovs.66.11.63