bims-mideyd 2026-03-15 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–03–15
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Characterization of the Effects of a Humanin Fragment Peptide (HNF14) in Age-Related Macular Degeneration.
Evaluation of risk promoting effects for age-related macular degeneration by estradiol.
Emerging strategies in drug repurposing for decreasing the risk of age-related macular degeneration.
The Inhibitory Effects of a Peripherally Restricted CB1 Receptor Antagonist on Myofibroblast Transdifferentiation of Human Retinal Pigment Epithelial Cells.
Violet-Blue Light Photobiological Effect on Cultured Corneal and Pigment Retinal Cells.
Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies.
Giant Retinal Pigment Epithelium Tear Secondary to Hypotony After Trabeculectomy for Open-Angle Glaucoma With Preoperative Untreated Choroidal Neovascularization: A Case Report.

J Clin Med. 2026 Feb 24. pii: 1686. [Epub ahead of print]15(5):

Characterization of the Effects of a Humanin Fragment Peptide (HNF14) in Age-Related Macular Degeneration.

Sonali Nashine, M Cristina Kenney.

  Background: Age-related macular degeneration (AMD) is a leading cause of vision loss and is strongly associated with mitochondrial dysfunction in retinal pigment epithelial cells. Mitochondrial-derived peptides, including Humanin and its analogs, have demonstrated cytoprotective effects in AMD-related cellular models. However, the effects of shorter Humanin-derived fragments in disease-specific mitochondrial models remain incompletely characterized. Methods: Transmitochondrial retinal pigment epithelial cybrid cell lines containing mitochondria from AMD patients or age-matched normal donors were treated with HNF14, a 14-amino acid Humanin fragment peptide. Cellular metabolic activity, cytotoxicity, oxidative stress, apoptotic signaling, inflammatory markers, angiogenic factor expression, and amyloid-β1-42-induced apoptosis were evaluated using biochemical assays, protein analyses, and live-cell imaging approaches. Results: HNF14 treatment was associated with improved metabolic activity and reduced cytotoxicity in AMD cybrids, with minimal effects in normal cybrids. HNF14 significantly reduced intracellular and mitochondrial oxidative stress, suppressed apoptotic and inflammatory markers, and decreased VEGF-A protein expression in AMD cybrids. In addition, HNF14 attenuated amyloid-β1-42-induced apoptotic signaling in AMD cybrids. These effects were selective for cybrids containing AMD-derived mitochondria. Conclusions: This study demonstrates that HNF14 mitigates mitochondrial and cellular stress responses in AMD transmitochondrial cybrid cells. The findings indicate that a short Humanin-derived fragment retains cytoprotective activity in a disease-specific mitochondrial context and support further investigation of mitochondrial-derived peptides as modulators of mitochondrial dysfunction relevant to AMD pathophysiology.

Keywords:  AMD; HNF14; Humanin; Humanin G; age-related macular degeneration; peptide

DOI:  https://doi.org/10.3390/jcm15051686
PLoS One. 2026 ;21(3): e0340477

Evaluation of risk promoting effects for age-related macular degeneration by estradiol.

Inga-Marie Pompös, Dietrich Polenz, Norbert Kociok, Silvia Winkler, Olaf Strauß.

Early menopause increases the risk for age-related macular degeneration (AMD), the most common cause of vision loss in industrialized countries. The supplementation with estradiol reduces the risk in these cases and suggesting that estradiol deficiency is a mediator of the risk association. We investigated rat models of estradiol deficiency mimicking either biological ageing (22 months of age) or early menopause by ovariectomy and age of 22 months. Serum analysis of gonadal hormones in both models showed the expected reduction in estradiol levels compared to 6 months old controls but also increases in progesterone, corticosterone and dehydroepiandrosterone sulfate (DHEA-S). Comparing the two estradiol deficiency models, we found no differences except for DHEA-S that were reduced in ovariectomized rats. The hormone status was associated with degenerative changes in the retina with higher activity of mononuclear phagocytes and p16/p21-dependent senescence. Mainly the estrogen receptor beta (ERβ) expressing cells were affected by estradiol deficiency: ganglion cells, cells of the inner nuclear layer (INL) and retinal pigment epithelial cells. An exception are photoreceptors that were ERβ negative, showed stronger degeneration in ovariectomized rats compared to sham treated animals. We conclude that either biological or ovariectomy induced estradiol deficiency might not cause but rather promote mechanisms that lead to AMD. The phenotype depends on a broader spectrum of altered hormones than on estradiol alone. Photoreceptor degeneration and cellular senescence that were ERβ independent in ovariectomized rats suggest non-estradiol effects to increase AMD risk by early menopause.

DOI: https://doi.org/10.1371/journal.pone.0340477
Expert Opin Drug Discov. 2026 Mar;21(3): 339-354

Emerging strategies in drug repurposing for decreasing the risk of age-related macular degeneration.

Beryl Zhou, Nikita Mokhashi, Dimitra Skondra.

   INTRODUCTION: Vision loss in older adults is largely driven by age-related macular degeneration (AMD), characterized by progressive central visual field damage and functional decline. While current options for wet and dry AMD are limited and expensive, drug repurposing represents a promising strategy to accelerate the discovery of effective, accessible treatment by leveraging medications with established safety profiles. Notably, anti-diabetic agents including metformin, sulfonylureas, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and insulin have emerged as modulators of the retinal pigment epithelium (RPE) function, photoreceptors, and retinal vascular integrity.
AREAS COVERED: This review highlights the roles of oxidative stress, inflammation, and complement-mediated immune dysregulation in AMD pathogenesis, alongside preclinical data demonstrating metformin's protective effects via AMP-activated protein kinase (AMPK) activation. Population-based studies and meta-analyses further suggest a modest reduction in AMD risk associated with metformin use in both diabetic and non-diabetic cohorts. Additional pharmacological agents include statins, glyburide, L-DOPA, fluoxetine, dimethyl fumarate, and nutraceuticals such as curcumin, melatonin, and N-acetylcysteine.
EXPERT OPINION: Early AMD prevention through repurposed therapeutics, guided by AI-driven design and systems biology, may enable personalized care via multimodal risk stratification incorporating genetic, metabolomic, and microbiome data. Rigorous, stratified clinical trials integrating bioinformatics and precision medicine are essential to validate the most effective candidates.

Keywords:  Age-related macular degeneration; drug repurposing; metformin; ophthalmology; retina

DOI:  https://doi.org/10.1080/17460441.2026.2635492
Cells. 2026 Feb 27. pii: 418. [Epub ahead of print]15(5):

The Inhibitory Effects of a Peripherally Restricted CB1 Receptor Antagonist on Myofibroblast Transdifferentiation of Human Retinal Pigment Epithelial Cells.

Dandan Zhao, Vishaka Motheramgari, Sarah H Shrader, Wei Wang, Shigeo Tamiya, Zhao-Hui Song.

  Myofibroblasts derived from retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of retinal fibrotic conditions such as proliferative vitreoretinopathy (PVR). Upon exposure to growth factors and cytokines such as TNF-α and TGF-β (TNT), RPE cells undergo epithelial-mesenchymal transition and subsequent transdifferentiation to contractile myofibroblasts. In this study, the effects of JD5037, a peripherally restricted CB1 antagonist, on myofibroblast transdifferentiation of primary cultures of human RPE cells were assessed. JD5037 significantly reduced TNT-induced, RPE cell-mediated collagen gel contraction, an indicator of myofibroblast function, in a concentration-dependent manner. Western blot analysis showed that JD5037 attenuated TNT-induced expression of α-SMA and fibronectin, two molecular markers of myofibroblasts. Furthermore, siRNA knockdown of CB1 cannabinoid receptor partially inhibited TNT-induced myofibroblast transdifferentation of human RPE cells and eliminated the inhibitory effects of JD5037 on myofibroblast transdifferentiation. These data demonstrate, for the first time, that peripherally restricted antagonists, such as JD5037, targeting the CB1 cannabinoid receptor have therapeutic potential for PVR and other retinal fibrotic conditions.

Keywords:  CB1 cannabinoid receptor; myofibroblast; retinal pigment epithelial cells

DOI:  https://doi.org/10.3390/cells15050418
Int J Mol Sci. 2026 Mar 08. pii: 2489. [Epub ahead of print]27(5):

Violet-Blue Light Photobiological Effect on Cultured Corneal and Pigment Retinal Cells.

Valerio Ciccone, Davide Amodeo, Gaia Papale, Alessandro Puccio, Marco Tani, Gabriele Cevenini, Lucia Morbidelli, Gabriele Messina.

  Artificial optical radiation, spanning from 100 nm to 1 mm, encompasses ultraviolet (UV) and infrared (IR) light. UV light is well known for its risks on the skin and eyes. Recently, there has been growing interest in light at 405 nm (violet-blue light, VBL) due to its antimicrobial properties and perceived safety for mammalian cells when administered in controlled amounts. This research delved into the impact of 405 nm VBL on corneal and retinal pigment epithelial cell cultures. ARPE-19 and corneal BCE C/D 1b cells were exposed to VBL for varying doses, according at different exposure times, to evaluate cell viability, oxidative stress levels and apoptotic indicators. A 3D printed prototype with 14 LEDs centred at 405 nm wavelength was used to ensure uniform distribution of light during exposure. Cell viability was assessed using the MTT assay, measurement of oxygen species (ROS) production was carried out, and Western blot analysis was employed to study catalase and SOD-1 expression and apoptotic marker activation. Exposure to 405 nm VBL for both term (3 h) and prolonged durations (9 h) led to a weak decrease in cell viability in ARPE-19 cells, whereas the effect on BCE C/D 1b cells was negligible. There was no increase in ROS production, with catalase and SOD-1 expression remaining stable, suggesting no pro-oxidative stress effects in these models. Moreover, no activation of caspase-3 and accumulation of cytochrome C were found. Based on our results, exposure to 405 nm light at regulated levels does not pose a threat to the viability of the tested cell lines and does not lead to oxidative stress and apoptosis under these conditions. These results suggest a favourable cytocompatibility profile for these specific ocular cell models, laying a foundation for further investigations into its ocular safety.

Keywords:  405 nm wavelength; apoptosis; cell viability; corneal cells; eye safety; oxidative stress; photobiological risk assessment; pigment retinal cells; violet-blue light

DOI:  https://doi.org/10.3390/ijms27052489
Cells. 2026 Mar 04. pii: 457. [Epub ahead of print]15(5):

Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies.

Laura Siles, Sheila Ruiz-Nogales, Pilar Méndez-Vendrell, Esther Pomares.

  Gene editing, particularly CRISPR/Cas technology, represents a promising approach for the treatment of rare genetic diseases, including inherited retinal dystrophies, for which effective therapies are largely unavailable. Despite extensive research investigating gene editing across a wide range of cell types, transient delivery of CRISPR/Cas components and efficient homology-directed repair (HDR) in differentiated cells remain challenging. In this study, we employed hiPSCs derived from patients with Stargardt disease or Best disease, carrying pathogenic variants in ABCA4 or BEST1, respectively, to explore gene editing in human models. CRISPR/Cas9 and Cas12 nucleases were delivered into hiPS-derived retinal pigment epithelium (RPE) and retinal organoids using lipoplexes and compared with electroporation. We evaluated transfection efficiency, sgRNA-mediated DNA cleavage, and HDR-based correction. Precise repair of the pathogenic BEST1 variant was successfully achieved in hiPS-derived RPE cells using both nucleases, with Cas12 yielding the highest efficiency, exceeding 10% of HDR correction. Edited RPE cells preserved normal morphology and expressed specific maturity markers. In contrast, retinal organoids exhibited moderate transfection efficiency but showed no detectable CRISPR/Cas-induced DNA cleavage, highlighting the need for further optimization of gene editing in more complex cellular tissues. This study demonstrates, for the first time, precise correction of a single-nucleotide mutation in patient-derived RPE using CRISPR/Cas9 and Cas12 delivered using lipoplexes. These findings underscore the therapeutic potential of CRISPR/Cas-based strategies for inherited retinal dystrophies and provide a proof of concept for future clinical approximations.

Keywords:  ABCA4; BEST1; Best disease; CRISPR; Stargardt disease; gene editing; inherited retinal dystrophies; lipoplexes; retinal organoids; retinal pigment epithelium

DOI:  https://doi.org/10.3390/cells15050457
Cureus. 2026 Feb;18(2): e103122

Giant Retinal Pigment Epithelium Tear Secondary to Hypotony After Trabeculectomy for Open-Angle Glaucoma With Preoperative Untreated Choroidal Neovascularization: A Case Report.

Tsuyoshi Matsuno, Ryo Tomita, Jun Takeuchi, Koji M Nishiguchi, Kenya Yuki.

  Retinal pigment epithelium (RPE) tears are frequently observed following anti-vascular endothelial growth factor therapy for age-related macular degeneration. While rare, giant RPE tears have also been reported secondary to choroidal detachment (CD) induced by postoperative hypotony after trabeculectomy (TLE). Although mechanical stress on the RPE is considered a common underlying factor in both scenarios, the exact mechanisms remain unclear. This report describes a case of a giant RPE tear originating from the site of a previously untreated choroidal neovascularization (CNV) following TLE. A 65-year-old male underwent TLE for intraocular pressure (IOP) control in his left eye with primary open-angle glaucoma. Preoperative IOP was 39 mmHg, and fundus examination revealed untreated CNV and sub-RPE hemorrhage. The scleral flap sutures were sequentially laser lysed on postoperative days two and four, as the postoperative IOP remained stable between 12 and 14 mmHg. On postoperative day seven, IOP decreased to 4 mmHg, and CD was observed. Following observation, the IOP increased to 7 mmHg on postoperative day 10, revealing a giant RPE tear and serous retinal detachment (SRD). An additional scleral flap suture was performed on the same day, and the IOP subsequently stabilized around 10 mmHg. During follow-up, the SRD spontaneously resolved by postoperative day 41, while the RPE tear persisted. Visual field testing revealed worsening of visual field defects compared to preoperative findings, with defects corresponding to the location of the RPE tear. The rapid IOP reduction following TLE may have induced mechanical stress on a vulnerable RPE region affected by CNV, leading to the RPE tear. A rapid IOP reduction may increase the risk of an RPE tear when vulnerable RPE areas exist due to CNV or other factors; therefore, careful preoperative evaluation for vulnerable RPE regions and cautious perioperative IOP management should be considered.

Keywords:  choroidal neovascularization; intraocular pressure; primary open angle glaucoma; retinal pigment epithelium tear; serous retinal detachment; trabeculectomy

DOI:  https://doi.org/10.7759/cureus.103122