bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2025–05–18
six papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington



  1. Med Microbiol Immunol. 2025 May 13. 214(1): 22
      The pathological basis of many visual disorders involves the abnormal viability and migration of retinal pigment epithelium (RPE) cells. Complement response disorder is a significant pathogenic factor causing some autoimmune and inflammation diseases. The complement activation product anaphylatoxin C5a signaling pathway may be associated with RPE cell dysfunction. This study aimed to analyze the molecular mechanisms by which C5a affects RPE cell viability and migration. Recombinant human complement component C5a protein stimulated RPE cells. Cell biological behavior, including cell viability, invasion, and migration were analyzed with Cell Counting Kit-8 and transwell methods. Bioinformatics analysis identified the differentially expressed genes (DEGs) involved in C5a-treated RPE cells based on RNA sequencing. SLC38A1 was knocked down or overexpressed by vector transfection to investigate its involvement in C5a-stimulated RPE cells. C5a promotes RPE cell viability and migration. C5a-induced DEGs are enriched in migration-associated pathways. C5a increased SLC38A1, and SLC38A1 knockdown or overexpression inhibited or promoted RPE cell viability and migration. Glutaminase inhibition abrogated the promoting effect of C5a and SLC38A1 on cell biological behaviors. METTL3-HNRNPC-mediated m6A modification mediated C5a-induced SLC38A1. C5a, METTL3, and SLC38A1 constituted a signaling axis in regulating cell biological behaviors of C5a-treated RPE cells. C5a promotes RPE cell viability and migration, and SLC38A1-mediated improved glutamine metabolism is the downstream signal pathway of the C5a complement pathway. The C5a complement system may target the SLC38A1 to promote RPE cell migration.
    Keywords:  Complement C5a; Glutamine metabolism; METTL3; Retinal pigment epithelium cell; SLC38A1
    DOI:  https://doi.org/10.1007/s00430-025-00832-4
  2. J Histotechnol. 2025 May 16. 1-11
      The retinal pigment epithelium (RPE) is associated with the emergence and development of diabetic retinopathy. Interestingly, a previous clinical study observed that the atrophy of RPE cells surrounding the optic disc in type 1 diabetic children were significantly less pronounced compared to normal children, contradicting current reports. In order to explore the molecular mechanisms behind this contradictory phenomenon, we conducted a series of experiments and reached the following results. First, RPE cells proliferation increased in a glucose concentration-dependent manner in vitro, accompanied by elevated Brachyury and CTGF protein expression, but decreased overall cell viability. Secondly, in vitro experiments and diabetes mouse models confirmed that insulin promoted RPE cell proliferation in high glucose concentrations by activating ERK1/2 phosphorylation. Furthermore, insulin down-regulated the expression of Brachyury and CTGF proteins, possibly reducing high-glucose‒induced damage to RPE cells. In conclusion, the effect of insulin treatment on the proliferation of RPE cells was significantly more significant than that of hyperglycemia, which may be related to the activation of Erk1/2 or reduction of RPE cell damage by inhibiting the occurrence of EMT.
    Keywords:  Retinal pigment epithelial; cell proliferation; diabetes; hyperglycemia; insulin
    DOI:  https://doi.org/10.1080/01478885.2025.2503520
  3. Arch Biochem Biophys. 2025 May 09. pii: S0003-9861(25)00148-1. [Epub ahead of print]770 110435
       BACKGROUND: Retinal degenerative diseases are important causes of blindness, and their pathogenesis is related to degenerative changes in the retinal pigment epithelium (RPE). αA-Crystallin (CRYAA) plays a role in maintaining cellular protein homeostasis and has been shown to protect the retina from stress; however, the detailed mechanisms involved in this protection are not known.
    METHODS: In vitro, ARPE-19 cells stably overexpressing CRYAA were generated from CRYAA-RPE cells. The effects of CRYAA overexpression on H2O2-induced RPE cell apoptosis were assessed via CCK-8 assays, flow cytometry, and reactive oxygen species (ROS) quantification. Differences in miR-155-5p levels between RPE and CRYAA-RPE cells were determined via RT‒qPCR. SIRT1 was predicted as a downstream target gene of miR-155-5p, and the relative luciferase activities of NC, miR-155-5p mimic with SIRT1 WT 3'-UTR and SIRT1 MT 3'-UTR reporter plasmids were determined using dual luciferase gene reporter assays. The expression of PI3K/AKT signaling pathway-related proteins was assessed by Western blotting. For in vivo experiments, a mouse model of retinal degeneration was constructed with sodium iodate, and the extent of retinal damage was assessed via histopathological analysis.
    RESULTS: In vitro experiments revealed that CRYAA overexpression significantly reduced apoptosis and decreased ROS levels as well as miR-155-5p expression. Additionally, the specific binding site of miR-155-5p to the SIRT1 3'-UTR was confirmed by bioinformatics prediction and a dual luciferase reporter assay. CRYAA overexpression increased SIRT1 expression, which further activated the PI3K/AKT signaling pathway, exerting a protective function. After the SIRT1 gene silencing or miR-155-5p overexpression, the PI3K/AKT signaling pathway was inhibited correspondingly. In vivo experiments revealed that vitreous Cryaa-AAV injection alleviated sodium iodate-induced retinal degeneration in mice, significantly improving retinal function.
    CONCLUSIONS: CRYAA activates the PI3K/AKT signaling pathway by decreasing miR-155-5p expression and increasing SIRT1 level, which protects RPE cells from apoptosis. These findings provide a new approach for the treatment of retinal degenerative diseases.
    Keywords:  Apoptosis; PI3K/AKT signaling pathway; Retinal pigment epithelium; SIRT1; miR-155–5p; αA-crystallin
    DOI:  https://doi.org/10.1016/j.abb.2025.110435
  4. Sci Rep. 2025 May 15. 15(1): 16849
      Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly, and the role of chaperonin containing TCP1 subunit 2 (CCT2) remains unclear. This study aims to elucidate the mechanistic link between CCT2 and AMD, contributing to improved understanding and potential therapeutic strategies. Retinal and RPE-Choroid transcriptome array data from 130 AMD patients and 121 normal donors (GSE29801 dataset) were reanalyzed to assess CCT2 expression across different AMD subtypes, age groups, and genders. Single-sample gene set enrichment analysis was performed to explore correlations with autophagy-related genes and other established AMD causes. Additionally, CCT2 expression was validated in sodium iodate (NaIO₃)-induced 661 W cells (photoreceptor-like cells) using quantitative real-time PCR (qRT-PCR). CCT2 was significantly enriched in advanced AMD retinas compared to intermediate stages in retina (both macular and extramacular) and early stages in extramacular retina (p < 0.05). NaIO3-treated 661 W cells exhibited a similar expression trend, confirming transcriptomic findings. CCT2 is significantly upregulated in advanced AMD and may contribute to drusen degradation. It shows potential as both a biomarker and an independent diagnostic indicator, particularly for advanced-stage AMD.
    Keywords:  Age related macular degeneration; Autophagy; CCT2; Drusen; Neurodegeneration
    DOI:  https://doi.org/10.1038/s41598-025-01907-1
  5. Aging Cell. 2025 May 15. e70107
      Aging-related retinal degeneration and vision loss have been severely affecting the elderly worldwide. Previously, we showed that the m6A reader YTHDF2 is a negative regulator for dendrite development and protection of retinal ganglion cells (RGC) in mice. Here, we further show that conditional ablation of Ythdf2 protects the retina from RGC dendrite shrinking and vision loss in aged mice. Additionally, we identify Hspa12a and Islr2 as the potential YTHDF2 target mRNAs mediating these effects. Together, our results indicate that the m6A reader YTHDF2 regulates retinal degeneration caused by aging, which might provide important therapeutic potential for developing new treatment approaches against aging-related vision loss.
    Keywords:  YTHDF2; aging; dendrite; m6A; retinal degeneration; visual acuity
    DOI:  https://doi.org/10.1111/acel.70107
  6. Front Cell Dev Biol. 2025 ;13 1586240
      Glaucoma is a complex disease of the optic nerve leading to vision loss and blindness, with high worldwide incidence and disproportionate prevalence in older populations. Primary open-angle glaucoma, caused by a reduction in outflow of aqueous humor through the trabecular meshwork, is the most common subset of the disease, though its underlying molecular mechanisms are not well understood. While increased intraocular pressure is the most common risk factor in glaucoma progression, the disease is ultimately characterized by the loss of retinal ganglion cells (RGCs) and destruction of the optic nerve. Given the irreversibility of RGC death, neuroprotection of RGCs is a promising avenue of glaucoma prevention and treatment. The caspase family of proteins are integral members of the apoptotic death cascade. They have been shown to play a significant role in RGC death in numerous models of retinal injury. Direct inhibition of several caspase family members, through targeted siRNAs and peptidomimetics, demonstrate promising capacity to reduce caspase expression and preserve RGCs following intraocular pressure increase or optic injury. A wide variety of alternative therapeutics targeted for RGC survival, including neurotrophins, immunomodulators, cytoprotectants, and endogenous hormones, also display indirect caspase-inhibiting capabilities. Following intraocular pressure increase or external retinal injury, both direct and indirect caspase inhibitors elicit higher RGC counts, increased RGC layer thickness, and attenuation of RGC damage, clearly demonstrating the neuroprotective abilities of caspase inhibitors. Caspase inhibition, particularly by direct approaches of siRNA or peptidomimetic-based therapeutics, has the potential to achieve substantial neuroprotection in the glaucomatous eye.
    Keywords:  caspase; glaucoma; neuroprotection; optic nerve; peptidomimetic inhibitor; retinal cell death; retinal ganglion cell
    DOI:  https://doi.org/10.3389/fcell.2025.1586240