bims-mideyd 2026-10-18 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–10–18
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Organelle Crosstalk: Mitochondria and Endoplasmic Reticulum in Macular Degeneration.
The synergistic effects of resveratrol and nicotinamide on cell proliferation, apoptosis, and SIRT1 gene expression in human retinal pigment epithelial cells.
Glycocalyx-binding and cell-penetrating peptide-modified nanomicelles for enhanced ocular delivery of quercetin and retinal protection in a dAMD model.
Metabolic impact of bisphenol A on retinal pigment epithelium: disturbed energy pathways and antioxidant response in ARPE-19 cells.
Therapeutic Window of AAV-SIRT1 Gene Therapy in Mouse Models of Optic Nerve Degeneration.
A protease-resistant D-amino acid αA-crystallin mini-chaperone with enhanced chaperone and antioxidant activities protects against amyloid-β proteotoxicity.
A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice.

J Ophthalmol Res. 2026 Sep;9(3): 60-67

Organelle Crosstalk: Mitochondria and Endoplasmic Reticulum in Macular Degeneration.

Iffat Alam, Ayeshah Hussain, Devendra K Agrawal.

  Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss characterized by progressive retinal pigment epithelium (RPE) dysfunction, mitochondrial damage, oxidative stress, and chronic inflammation. While mitochondrial dysfunction is a known contributor to AMD, the contribution of the endoplasmic reticulum (ER) has not been fully explored. Mitochondrial associated membranes (MAMs) are regions of the mitochondria which are in direct contact with the ER and are critical areas for regulating essential cellular functions including calcium signaling, mitochondrial dynamics, and apoptosis. Dysfunction of these critical sites may lead to progressive retinal degeneration through the production of reactive oxygen species (ROS), calcium overload, and inflammasome activation in RPE cells. The study was conducted as a comprehensive critical review article on the subject. Findings are reported on the connection between the mitochondria and ER, specifically through MAM dysfunction, in macular degeneration. Overall, this critical review article discusses the pathophysiology of macular degeneration with the mechanistic insights into MAM deregulation and decoding the structural and functional breakdown of MAMs. Understanding the role of MAM-mediated signaling in AMD may identify potential therapeutic targets aimed at restoring mitochondrial resilience and retinal homeostasis.

Keywords:  Age-Related Macular Degeneration (AMD); Endoplasmic Reticulum; Epithelium; Macular Degeneration; Mitochondria; Mitochondrial Associated Membranes (MAMs); Mitochondrial Dysfunction; Organelle Crosstalk; Oxidative Stress; Retinal Pigment Epithelium (RPE)

DOI:  https://doi.org/10.26502/fjor.2644-002400117
Tissue Cell. 2026 Oct 12. pii: S0040-8166(26)00731-7. [Epub ahead of print]104(Pt 3): 104035

The synergistic effects of resveratrol and nicotinamide on cell proliferation, apoptosis, and SIRT1 gene expression in human retinal pigment epithelial cells.

Tuğba Keskin, Sengul Tural, Ozlem Eski Yucel.

  The aim of our study is to evaluate the effects of Resveratrol and Nicotinamide on cell proliferation, viability, apoptosis and SIRT1 gene expression in human retinal pigment epithelial cells (RPE), with relevance to age-related macular degeneration (AMD). Healthy RPE cells were exposed to moderate oxidative stress, then treated with resveratrol (50-100-150 μmol/L) and nicotinamide (1-5-10 mM/L), both separately and in combination, for 24, 48, and 72 h. Morphological changes and cell density were examined using inverted microscopy to complement functional data. The most significant results were achieved with 72 h of combined treatment with 100 μmol/L resveratrol and 1 mM/L nicotinamide, showing increased cell viability and proliferation (p < 0.001), decreased apoptosis+necrosis values (p < 0.001), and elevated SIRT1 expression (p < 0.001). This combination was non-cytotoxic to healthy RPE cells (p > 0.05) and more effective than separate treatments. The combined application caused SIRT1 gene expression levels similar to healthy controls (p > 0.05). To confirm functional dependency on SIRT1, targeted gene silencing was performed using SIRT1 siRNA. Compared to the negative control group, SIRT1 silencing resulted in a 25.58-fold downregulation of SIRT1 mRNA, accompanied by a 5.28-fold upregulation of pro-apoptotic Bax and a 3.91-fold downregulation of anti-apoptotic Bcl-2 (p < 0.001), effectively reversing the cytoprotective effects of the co-treatment. These findings demonstrate that RV+NAM co-treatment exerts robust synergistic protection against oxidative stress-induced apoptosis in RPE cells through SIRT1-dependent mechanism, offering a promising therapeutic strategy for dry AMD. This is the first study to investigate the effects of this specific dose combination in a dry AMD model.

Keywords:  Age related macular degeneration; Nicotinamide; Resveratrol; SIRT1 gene

DOI:  https://doi.org/10.1016/j.tice.2026.104035
Int J Pharm. 2026 Oct 10. pii: S0378-5173(26)00960-9. [Epub ahead of print]705 127512

Glycocalyx-binding and cell-penetrating peptide-modified nanomicelles for enhanced ocular delivery of quercetin and retinal protection in a dAMD model.

Shuyao Li, Qinghua Yang, Yadi Zhu, Tingting Li, Daniel Scherman, Wei Li, Zhoujiang Chen, Sanjun Shi, Hanmei Li, Liang Zou.

  Dry age-related macular degeneration (dAMD) is a highly prevalent degenerative retinal disease. Quercetin, a bioactive ingredient in traditional Chinese medicine, can mitigate the oxidative stress that helps drive dAMD; however, its low water solubility and poor corneal permeability limit its efficacy. We developed dual-functional polymeric micelles (PMs) co-conjugated with a glycocalyx-binding peptide (GBP) and a cell-penetrating peptide (TAT) for the enhanced topical ocular delivery of quercetin (QUE), named GT-PMs/QUE. The GT-PMs/QUE exhibited a particle size of 46.25 ± 3.05 nm and a zeta potential of -5.64 ± 0.92 mV. GT-PMs exhibited significantly higher cellular uptake efficiency than the unmodified group (PMs) and single-peptide modified groups (GBP-PMs and TAT-PMs). In the sodium iodate-induced oxidative damage model of adult retinal pigment epithelial cell line-19 (ARPE-19) cells, the GT-PMs/QUE treatment group showed significantly reduced ROS and MDA levels along with markedly increased SOD, CAT, and GSH activities that approached normal control levels compared to the model group. In a mouse model of dAMD, GT-PMs/QUE greatly improved the bioavailability of quercetin delivered via eye drop administration and attenuated sodium iodate-induced retinal damage. This study provides a theoretical and experimental basis for enhanced ocular delivery of quercetin and protection against dAMD-related retinal damage.

Keywords:  Age-related macular degeneration; Eye drops; Micelles; Ocular surfaceglycocalyx; Penetrating peptides; Quercetin

DOI:  https://doi.org/10.1016/j.ijpharm.2026.127512
Drug Chem Toxicol. 2026 Oct 11. 1-11

Metabolic impact of bisphenol A on retinal pigment epithelium: disturbed energy pathways and antioxidant response in ARPE-19 cells.

Tuba Tüylü Küçükkılınç, Ozan Kaplan, Seyhan Türk, Emine Koç, Emine Merve Yıldırım, Mustafa Çelebier.

  Bisphenol A (BPA) is a widely utilized endocrine-disrupting chemical that has been associated with metabolic dysregulation in various tissues. Nevertheless, its impact on ocular metabolism remains insufficiently understood. This study aims to investigate the metabolic effects of BPA exposure in ARPE-19 retinal pigment epithelial cells using untargeted metabolomics. ARPE-19 cells were exposed to 100 µM BPA for 24 hours, and cytotoxicity, intracellular reactive oxygen species (ROS) levels and glutathione metabolism parameters were identified. Metabolic alterations were analyzed utilizing liquid chromatography-quadrupole time-of-flight mass spectrometry (Q-TOF LC/MS). Principal component analysis (PCA), volcano plots, heatmaps, and pathway enrichment analysis were conducted to identify significantly altered metabolites and pathways. BPA exposure led to notable metabolic changes, including alterations in the tricarboxylic acid (TCA) cycle, β-oxidation, nucleoside metabolism, and amino acid metabolism. Key metabolite changes included increased levels of glutamine, pyroglutamic acid, anserine, and adenosine 2',3'-cyclic phosphate, suggesting oxidative stress and metabolic adjustment. Pathway analysis identified significant changes in arachidonic acid metabolism and pyrimidine metabolism, indicating oxidative stress and metabolic compensation due to BPA exposure. The findings underscore the metabolic risks of BPA exposure to retinal health and necessitate further validation through targeted metabolomics and in vivo studies.

Keywords:  Bisphenol A (BPA); energy metabolism; metabolomics; oxidative stress; retinal pigment epithelium (RPE)

DOI:  https://doi.org/10.1080/01480545.2026.2697203
Transl Vis Sci Technol. 2026 Oct 05. 15(10): 17

Therapeutic Window of AAV-SIRT1 Gene Therapy in Mouse Models of Optic Nerve Degeneration.

Brahim Chaqour, Jennifer C Pham, Jipeng Yue, Kimberly Dine, Fangming Jin, Gui-Shuang Ying, Jean Bennett, Kenneth S Shindler, Ahmara G Ross.

Purpose: Optic neuropathies involve progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision deficits. While pretreatment with drugs or gene therapy that upregulate sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, has shown neuroprotective effects, its effectiveness when administered after disease onset remains uncertain. We investigated whether adeno-associated virus (AAV)-mediated SIRT1 overexpression in RGCs can provide post-onset neuroprotection in preclinical models of optic neuropathy.
Methods: RGC degeneration was induced in C57BL/6 mice (8-10/group) using two models: elevated intraocular pressure via intracameral magnetic microbeads (glaucoma model), and myelin oligodendrocyte glycoprotein immunization to induce optic neuritis in an experimental autoimmune encephalomyelitis (EAE model). Mice received intravitreal injections of either control AAV2 or AAV2-SIRT1, which drives SIRT1 expression under the γ-synuclein promoter. Treatment was delivered either 2 weeks before, at, or 1 week after disease onset. We assessed RGC survival and function by immunolabeled RGC counting and optokinetic response, respectively.
Results: Intraocular pressure elevation and EAE induction reduced RGC counts and optokinetic response. In the glaucoma model, AAV2-SIRT1 administered before or after onset preserved visual function and increased RGC survival. In the EAE model, SIRT1 therapy significantly increased RGC survival at all time points, although visual function was not significantly improved.
Conclusions: SIRT1 gene therapy confers robust RGC neuroprotection and potentially preserves visual function when delivered before or after disease onset in the models of ocular hypertension and optic neuritis.
Translational Relevance: Our study underscores the translational relevance of SIRT1-based interventions and suggests their potential to avert vision loss in optic neuropathies.

DOI: https://doi.org/10.1167/tvst.15.10.17
Free Radic Biol Med. 2026 Oct 13. pii: S0891-5849(26)01223-2. [Epub ahead of print]257 397-408

A protease-resistant D-amino acid αA-crystallin mini-chaperone with enhanced chaperone and antioxidant activities protects against amyloid-β proteotoxicity.

Swati Srivastava, Puttur Santhoshkumar, Tenzin Tender, Krishna Sharma.

  Protein misfolding, aggregation, and oxidative stress contribute to aging and numerous neurodegenerative diseases, including Alzheimer's disease. Although the αA-crystallin-derived mini-chaperone peptide suppresses protein aggregation, its therapeutic potential is limited by susceptibility to proteolytic degradation. Here, we synthesized a protease-resistant analog composed entirely of D-amino acids (D-MC-αA) and compared its biochemical and biological properties with those of the parent peptide (MC-αA). Chaperone activity was assessed using two aggregation-prone model proteins, antioxidant activity by inhibition of Cu2+-mediated oxidation of ascorbic acid, and proteolytic stability by enzymatic digestion followed by reverse-phase HPLC. Cytoprotective and membrane-protective activities were evaluated using melittin-induced cytotoxicity in retinal pigment epithelial cells and hemolysis of human red blood cells. Peptide uptake, lifespan, thermotolerance, and protection against amyloid-β toxicity were evaluated in Caenorhabditis elegans (C. elegans). D-MC-αA exhibited approximately threefold greater chaperone activity than MC-αA, completely resisted enzymatic degradation, and more effectively inhibited Cu2+-mediated ascorbic acid oxidation. Both peptides protected retinal cells against melittin-induced injury and reduced red blood cell hemolysis. The mini-chaperone was efficiently taken up by C. elegans, and both peptides significantly extended lifespan, enhanced thermotolerance, delayed amyloid-β-induced paralysis, and prolonged survival without adversely affecting feeding behavior or reproduction. D-MC-αA provided greater protection than MC-αA against amyloid-β-induced paralysis and mortality. Collectively, these findings demonstrate that all-D-amino acid substitution confers proteolytic resistance, enhances chaperone and antioxidant activities, and preserves cytoprotective function, supporting further development of D-MC-αA for disorders associated with protein misfolding, oxidative stress, and amyloid toxicity.

Keywords:  Aging; Amyloid; Antioxidant; Chaperone; D-amino acid peptide; Protein aggregation; Proteostasis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.032
bioRxiv. 2026 Sep 30. pii: 2026.09.29.755187. [Epub ahead of print]

A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice.

Yuancheng Ryan Lu, Han Shen, Kathrin Kajderowicz, Jiahe Ai, Yi Hua Chen-Neumann, Yan Hu, Alexander Tyshkovskiy, Qiannuo Lou, Tianwei Dong, Louisa Grauvogel, Zhaoyi Chen, James C Cameron, Ximeng Li, Shintaro Shirahama, Michael Bligh, Shurong Hou, Jessica Chin, Mauro W Costa, Jiwon Ryu, Ruchi Sharma, Matthias Mann, Kapil Bharti, Catherine Bowes Rickman, Vadim N Gladyshev, Meredith Gregory-Ksander, Bruce R Ksander, Jonathan Weissman.

Aging is a complex process, yet therapeutic discovery has largely relied on hypothesis-driven testing of individual targets. Here, we performed an unbiased genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are particularly vulnerable to oxidative damage with age. The screen identified nine protective ORFs, including antioxidant factors and a regulator of epithelial-to-mesenchymal transition. Notably, we also identified three factors that reduce transcriptomic age, including the cardiac transcription factor NKX2-5. NKX2-5 conferred robust oxidative resilience in vitro and in vivo . Domain dissection showed that its homeodomain was dispensable for resilience, enabling development of NKX2-5ΔHD, which retained protective activity without detectable toxicity over 14 months. In middle-aged mice, subretinal NKX2-5ΔHD restored visual and electrophysiological function, and its systemic delivery improved grip strength and reduced frailty in late-aged mice. These findings establish genome-scale ORF screening as a strategy to discover transferable resilience factors that can be reengineered to counter age-related functional decline across tissues.

DOI: https://doi.org/10.64898/2026.09.29.755187