bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2025–03–09
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington
  1. FTO-mediated Nrf2 demethylation alleviates high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells.
  2. Deciphering age-related transcriptomic changes in the mouse retinal pigment epithelium.
  3. Constitutive and Hypoxia-Induced VEGF Production by Cultured Uveal Melanocytes and Retinal Pigment Epithelial Cells.
  4. Safe CNV removal is crucial for successful hESC-RPE transplantation in wet age-related macular degeneration.
  5. Unraveling the role of neuregulin-mediated astrocytes-OPCs axis in the pathogenesis of age-related macular degeneration and Parkinson's disease.
  6. PDZK1 regulated by miR-145-5p protects against endothelial cell apoptosis and diabetic retinopathy by targeting mitochondrial function.
  7. FABP3 promotes cell apoptosis and oxidative stress by regulating ferroptosis in lens epithelial cells.
  1. Mol Biol Rep. 2025 Mar 07. 52(1): 289
    FTO-mediated Nrf2 demethylation alleviates high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells.
    Quan Cheng, Liqiong Zhou, Xinyu Fan, Minjun Ma, Chunhui Zhang, Xu Zha, Yuanping Zhang.
       BACKGROUND: N6-methyladenosine (m6A) modification contributes to the development of diabetic retinopathy (DR). This study aimed to reveal the role and downstream regulatory signaling of an m6A demethylase fat mass and obesity-associated gene (FTO) in high glucose-induced damage of retinal pigment epithelial cells.
    METHODS AND RESULTS: By stimulating ARPE-19 cells with different concentrations of glucose (0 mM-50 mM), we observed that FTO expression was significantly downregulated, while m6A modification level was upregulated in a glucose concentration-dependent manner in ARPE-19 cells. Then, ARPE-19 cells were transfected with FTO knockdown or overexpression vector, and administrated with high glucose (25mM) to perform functional verification experiments. FTO overexpression recovered cell viability, inhibited cell apoptosis, elevated GSH/GSSG ratio, but reduced MDA and ROS levels in high glucose-induced cells, while FTO knockdown further exacerbated high glucose-triggered oxidative stress and apoptotic cell death. Additionally, FTO overexpression upregulated the expression of NF-E2-related factor 2 (Nrf2) and activated the antioxidant heme oxygenase 1 (HO-1) signal through m6A demethylation on Nrf2 in high glucose-treated ARPE-19 cells. Finally, we proved that knockdown of Nrf2 or HO-1 reversed the protective effects of FTO overexpression on high glucose-treated ARPE-19 cells.
    CONCLUSION: Altogether, the study demonstrated that FTO ameliorates high glucose-triggered oxidative stress and cell apoptosis through activating the Nrf2/HO-1 signaling pathway in an m6A-dependent manner.
    Keywords:  Diabetic retinopathy; Fat mass and obesity-associated gene; Heme Oxygenase 1; N6-methyladenosine; NF-E2-related factor 2
    DOI:  https://doi.org/10.1007/s11033-025-10400-x
  2. Aging (Albany NY). 2025 Mar 04. null
    Deciphering age-related transcriptomic changes in the mouse retinal pigment epithelium.
    Sushil K Dubey, Rashmi Dubey, Kyungsik Jung, Alvaro G Hernandez, Mark E Kleinman.
      Aging of the retinal pigment epithelium (RPE) leads to a gradual decline in RPE homeostasis over time, significantly impacting retinal health. Understanding the mechanisms underlying RPE aging is crucial for elucidating the background in which many age-related retinal pathologies develop. In this study, we compared the transcriptomes of young and aged mouse RPE and observed a marked upregulation of immunogenic, proinflammatory, and oxidative stress genes in aging RPE. Additionally, aging RPE exhibited dysregulation of pathways associated with visual perception and extracellular matrix production. Research on aging in post-natal quiescent RPE is hindered by the absence of relevant in vitro models. Here, we evaluated an in vitro model of chronologically aged primary human RPE to address this gap and observed gene expression patterns comparable to native-aged RPE. Gene expression profiling in this model highlighted its potential utility in investigating cellular and molecular mechanisms of RPE aging and in screening of therapeutic compounds. In conclusion, our findings underscore the pivotal role of inflammation, immune activation, and oxidative stress in the aging RPE landscape and provide insights into why age increases the risk of retinal pathologies.
    Keywords:  chronological aging; inflammation; oxidative stress; retinal pigment epithelium; transcriptome
    DOI:  https://doi.org/10.18632/aging.206219
  3. Exp Eye Res. 2025 Mar 01. pii: S0014-4835(25)00089-2. [Epub ahead of print] 110318
    Constitutive and Hypoxia-Induced VEGF Production by Cultured Uveal Melanocytes and Retinal Pigment Epithelial Cells.
    Dan-Ning Hu, Ruihua Zhang, Codrin E Iacob, Andy Yao, Shun-Fa Yang, Chi-Chao Chan, Richard B Rosen.
      Constitutive secretion of VEGF is crucial for maintaining ocular circulation while hypoxia-induced VEGF secretion plays an important role in pathological neovascularization. Previous studies have highlighted the critical function of RPE cells in these situations. The role of uveal melanocytes (UM) in VEGF production, however, has not been well described. The aim of this study was to compare VEGF production from human RPE and UM cell lines obtained in pairs from 3 donors to minimize individual variability in cellular function. Cells were subjected to hypoxia, (1% oxygen environment) or chemical hypoxia (cobalt chloride, CoCl2) at different times or dosages, respectively. The effects of these treatments on the cell viability and cell proliferation were tested using MTT and cell counting with trypan blue testing. The production of VEGF and its main upstream factor (hypoxia-inducible factors-1α, HIF-1α) were measured in the conditioned culture medium and cellular extracts, by using ELISA analysis. Additionally, mRNA levels of VEGF and HIF-1α were quantified through real-time PCR analysis. The effects of CoCl2 on the expression of VEGF and HIF-1α in UM and RPE cells were also examined using flow cytometry. Hypoxia and COCL2 exposure did not affect cell viability and cell proliferation. This study revealed that the constitutive production of VEGF by RPE cells is significantly greater than from the UM. However, UM demonstrated a more robust response to high hypoxia or chemical hypoxic stimulation compared to RPE cells. The data suggests that while RPE cells play a critical role in constitutive VEGF production under normal conditions, UM may contribute significantly to the pathological increase in VEGF under severe ocular hypoxia. The observation that intraocular injection of CoCl2 to produce local chemical hypoxia, results in a significant increase of VEGF levels in intraocular fluids and tissues, has not been reported previously. While this model cannot currently test the in vitro results, it may help further our understanding of UM and RPE cells' roles in VEGF production in future studies using more advanced technologies in a well-established in vivo model.
    Keywords:  Hypoxia-inducible factors-1α; cobalt chloride; retinal pigment epithelial cells; uveal melanocytes; vascular endothelial growth factor
    DOI:  https://doi.org/10.1016/j.exer.2025.110318
  4. Stem Cell Reports. 2025 Feb 20. pii: S2213-6711(25)00028-1. [Epub ahead of print] 102424
    Safe CNV removal is crucial for successful hESC-RPE transplantation in wet age-related macular degeneration.
    Ying Xue Lv, Qi You Li, Ping Duan, Min Fang Zhang, Bo Liu, Shi Ying Li, Tong Tao Zhao, Hao Wang, Yong Liu, Zheng Qin Yin.
      Subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells has demonstrated therapeutic potential in macular degeneration. However, its efficiency is limited in wet age-related macular degeneration (wet AMD) due to choroidal neovascularization (CNV). To investigate the feasibility of hESC-RPE cell transplantation, we employed a surgical approach to induce retinal detachment, which allowed the removal of CNV lesions. After retinal reattachment, hESC-RPE cells were transplanted into the subretinal space. Ten patients were enrolled and divided into 2 groups. No retinal edema or CNV recurrence was observed in group 1 (7 patients without bleeding). Group 2 (3 patients with bleeding) had persistent fundus inflammation, and one patient experienced CNV recurrence. All patients were managed effectively without vision loss. These findings suggest that subretinal transplantation of hESC-RPE cells after CNV removal is safe and well tolerated; however, damage caused during CNV removal may trigger persistent inflammation and CNV recurrence. This study was registered at ClinicalTrials.gov (NCT02749734).
    Keywords:  cell therapy; fundus inflammation management; hESC-RPE tansplantation; surgical removal of CNV; wet AMD
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102424
  5. Sci Rep. 2025 Mar 01. 15(1): 7352
    Unraveling the role of neuregulin-mediated astrocytes-OPCs axis in the pathogenesis of age-related macular degeneration and Parkinson's disease.
    Shuyan Zhang, Cheng Zhang, Yinjian Zhang, Yibin Feng.
      Age-related macular degeneration (AMD) and Parkinson's disease (PD) are prevalent and debilitating conditions that lead to irreversible blindness and dyskinesia, respectively. Emerging evidences imply that retinal abnormalities may serve as early indicators for monitoring PD. This study endeavors to explore the complex interactions and focus on their shared molecular and pathological mechanisms. We employed a comprehensive approach by integrating single-cell RNA sequencing (scRNA-seq) datasets, obtained from dry AMD retinas and PD brain tissues, along with Weighted Gene Co-expression Network Analysis (WGCNA)-related computational analysis. Gene Set Enrichment Analysis (GSEA) was conducted to analyze PD-related genes within retinal ganglion cells in dry AMD. Cell-cell chat was utilized to predict intercellular communication and signaling pathways. Module eigengenes (MEs) were calculated to identify specific gene modules. Dysregulation of PALLD, FYN and ZMZ1 may lead to cell structural abnormalities, impaired mitochondrial functions, and increased susceptibility to neuroinflammation, contributing to the AMD and PD progression. Additionally, this study highlighted an astrocyte-oligodendrocyte precursor cell (OPCs) signaling axis mediated by Neuregulin (NRG), which is hypothesized to influence neuroinflammatory processes characteristic of dry AMD and PD pathogenesis. Notably, ME-salmon module associated with gene dysregulation exhibited a strong positive correlation with the ME-blue module, linked to neurodegenerative impairment, and the ME-yellow module, related to mitochondrial dysfunction. The comprehensive investigation on astrocytes-OPCs signaling axis, and the NRG signaling pathway advances our understanding of the intricate biological processes underpinning AMD and PD. This research underscores the critical importance about exploring glial-related cell interactions, providing valuable insights into potential novel therapeutic approaches for these complex diseases.
    Keywords:  Age-related macular degeneration; Computational machine analysis; Glial cells; Parkinson’s disease; Retina-brain axis
    DOI:  https://doi.org/10.1038/s41598-025-92103-8
  6. Exp Eye Res. 2025 Feb 26. pii: S0014-4835(25)00085-5. [Epub ahead of print]254 110314
    PDZK1 regulated by miR-145-5p protects against endothelial cell apoptosis and diabetic retinopathy by targeting mitochondrial function.
    Meixia An, Jialuo Huang, Jian Zhao, Lili Wang, Yanli Liu.
      Mitochondria are a focus of biomedical research because of their role in apoptosis and diabetic retinopathy (DR) initiation and progression. However, the detailed mechanisms underlying mitochondrial disorders and endothelial dysfunction during DR remain elusive. We identified PDZ domain containing 1 (PDZK1) as a key factor linking endothelial mitochondrial dysfunction and cell apoptosis during DR progression. PDZK1 was downregulated by high concentrations of glucose in human retinal capillary endothelial cells (HRCECs) and decreased in serum from patients with DR. PDZK1 knockout induced endothelial cell apoptosis and an irregular and disordered arrangement of retinal cells, aggravating DR. Moreover, PDZK1 loss impaired endothelial mitochondrial function with accumulated damaged mitochondria, decreased mitochondrial DNA (mtDNA) content, and increased reactive oxygen species (ROS) production. Mechanistically, mRNA sequencing showed that PDZK1 deficiency in endothelial cells interfered with mitochondrial function by increasing ATF4 (Activating Transcription Factor 4) expression. Further studies showed that PDZK1 was inhibited by miR-145-5p. The expression of miR-145-5p was significantly upregulated in the serum of patients with DR and HRCECs with high glucose concentration, leading to endothelial dysfunction and DR progression. Our results suggested that PDZK1 deficiency is crucial in mediating retinal endothelial cell apoptosis and is associated with mitochondrial dysfunction. PDZK1 overexpression by upstream miRNA, or its downstream molecule, ATF4, may represent novel therapeutic approaches for DR treatment.
    Keywords:  Diabetic retinopathy; Mitochondrial function; PDZK1
    DOI:  https://doi.org/10.1016/j.exer.2025.110314
  7. Free Radic Res. 2025 Mar 05. 1-14
    FABP3 promotes cell apoptosis and oxidative stress by regulating ferroptosis in lens epithelial cells.
    Qi Wang, Chunxiao Zhang, Bin Yu, Yanyan Zhang, Yuanyuan Guo.
      The purpose of this study is to investigate FABP3's biological function and potential mechanism in cataract. Treatment of H2O2 raised FABP3 expression. H2O2 decreased cell viability, enhanced apoptosis, promoted Bax and cleaved caspase-3 expression, inhibited Bcl-2 expression, enhanced the levels of IL-6, IL-1β, and TNF-α, raised MDA level, and decreased SOD and GSH levels in HLE-B3 cells. However, the effects of H2O2 on cell viability, apoptosis, inflammatory cytokines, and oxidative stress were reversed by FABP3 knockdown and aggravated by FABP3 overexpression. H2O2 increased the levels of lipid hydroperoxides and Fe2+, but reduced the expression of GPX4, SLC7A11, and Ferritin protein. Nevertheless, knockdown of FABP3 reversed the changes of lipid hydroperoxides, Fe2+, GPX4, SLC7A11, and Ferritin protein, and FABP3 overexpression caused the opposite results. In addition, the inhibition of FABP3 knockdown on cell apoptosis, inflammation, and oxidative stress was reversed by ferroptosis inducer (erastin), and the promotion of FABP3 overexpression on cell apoptosis, inflammation, and oxidative stress was reversed by ferroptosis inhibitor (Fer-1). Taken together, knockdown of FABP3 in lens epithelial cells treated with H2O2 restrained apoptosis, inflammation, and oxidative stress through regulating ferroptosis, suggesting that FABP3 might be a potential target for cataract treatment.
    Keywords:  FABP3; cataract; ferroptosis; oxidative stress
    DOI:  https://doi.org/10.1080/10715762.2025.2475390
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