bims-mideyd 2026-08-09 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–08–09
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Psalmotoxin-1, a novel TRPM2 channel antagonist, reduces age-related macular degeneration-caused mitochondrial oxidative damage and apoptosis in human retinal pigment epithelial (ARPE-19) cells.
Ginkgolide B protects retinal pigment epithelial cells from H2O2-induced oxidative stress and apoptosis by activating the AMPK/Nrf2 pathway.
Marine nutraceuticals from Mexican Pacific Sargassum targeting oxidative stress and inflammation in age-related macular degeneration.
3D epigenomic landscape of the human retinal pigment epithelium.
Cellular Senescence in Posterior Segment Neovascular Diseases: A Proposed Feed-Forward Amplification Model.
EGFR inhibition promotes functional engraftment and graft survival via donor-derived CHI3L1 in fetal RPE suspension transplantation.
N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity.

Graefes Arch Clin Exp Ophthalmol. 2026 Aug 06.

Psalmotoxin-1, a novel TRPM2 channel antagonist, reduces age-related macular degeneration-caused mitochondrial oxidative damage and apoptosis in human retinal pigment epithelial (ARPE-19) cells.

Dilek Özkaya, Mustafa Nazıroğlu.

   PURPOSE: Age-related macular degeneration (AMD) develops as a result of mitochondrial reactive oxygen species (mitROS) and apoptosis caused by increased Ca2+ influx via the overstimulation of transient receptor potential melastatin 2 (TRPM2). Psalmotoxin-1 (PSTX) has acid-sensing ion channel (ASIC) inhibitor and antioxidant actions in several cells. PSTX has been shown to modulate hypoxia-induced oxidative cytotoxicity and cell death in mouse eye cells by inhibiting ASIC-mediated Ca2+ influx; however, this mechanism does not apply to AMD. In this study, we investigated how PSTX inhibits TRPM2 to protect human retinal pigment epithelium - 19 (ARPE-19) cells against mitROS damage and apoptosis caused by sodium iodate (SoI).
MATERIALS AND METHODS: Control (CONT), 20 nM PSTX for 24 h, 10 mM SoI for 24 h, SoI + PSTX, and SoI + TRPM2 antagonist (25 µM N-(p-amylcinnamoyl) anthranilic acid, ACA) groups were induced in the ARPE-19 cells.
RESULTS: The ADP-ribose-induced TRPM2 current density, Fe2+, and H2O2-induced cytosolic Ca2+ concentrations were elevated by the SoI treatment. Additionally, its treatment increased the markers of apoptosis, caspases (caspase-3, -8, and - 9), oxidative stress, and mitochondrial membrane dysfunction while lowering glutathione (GSH), glutathione peroxidase (GSH-Px), and cell viability number. GSH, GSH-Px, and cell viability were enhanced, whereas oxidative stress and cell death indicators were decreased via TRPM2 inhibition by the treatments of PSTX and ACA.
CONCLUSION: The results of the preliminary study indicated that PSTX incubation blocked TRPM2-mediated Ca2+ signaling, reducing AMD-induced mitochondrial oxidant injury and cell death. PSTX, a new TRPM2 antagonist, may be utilized to treat oxidative stress and aberrant Ca2+ influx induced by AMD.

Keywords:  Age-related macular degeneration; Cell death; Mitochondrial oxidant injury; Psalmotoxin-1; TRPM2 cation channel

DOI:  https://doi.org/10.1007/s00417-026-07436-5
Front Med (Lausanne). 2026 ;13 1755596

Ginkgolide B protects retinal pigment epithelial cells from H2O2-induced oxidative stress and apoptosis by activating the AMPK/Nrf2 pathway.

Bei Zhan, Ran Xia, Liming Tao.

   Objective: To investigate whether Ginkgolide B (GB) protects retinal pigment epithelial cells (RPEs) from hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis, and to explore the potential involvement of the adenosine monophosphate-activated protein kinase α (AMPKα)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
Methods: Human RPEs were divided into the following groups: control, model (200 μmol/L H₂O₂ for 24 h), GB + H₂O₂, GB + H₂O₂ + Compound C (an AMPK inhibitor), H₂O₂ + Compound C, and GB alone. Cell viability, apoptosis, antioxidant parameters, and AMPKα/Nrf2 expression were assessed using the Cell Counting Kit-8 (CCK-8) assay, flow cytometry, colorimetric biochemical assays, transmission electron microscopy (TEM), quantitative polymerase chain reaction (PCR), and Western blot.
Results: TEM showed that GB attenuated H₂O₂-induced mitochondrial swelling and cristae disruption, which were reversed by Compound C. Compared with the model group, the GB + H₂O₂ group exhibited increased cell viability, decreased apoptosis, elevated activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), as well as increased glutathione (GSH) content, and reduced malondialdehyde (MDA) (all p < 0.05), though protein carbonyl (PC) levels showed no significant amelioration. All protective effects were attenuated by Compound C. In the GB-alone group, the percentage of apoptotic cells, Nrf2 mRNA expression, and all other parameters did not differ significantly from those in the control group.
Conclusion: GB was associated with protection of RPEs against H₂O₂-induced oxidative stress and apoptosis. Because these protective effects were attenuated by pharmacological inhibition of AMPK, the findings suggest that AMPK/Nrf2 signaling may contribute to the cytoprotective actions of GB. However, additional mechanistic studies are required to confirm the involvement of this pathway.

Keywords:  AMPK/Nrf2; Ginkgolide B; apoptosis; oxidative stress; retinal pigment epithelial cells

DOI:  https://doi.org/10.3389/fmed.2026.1755596
Front Nutr. 2026 ;13 1888072

Marine nutraceuticals from Mexican Pacific Sargassum targeting oxidative stress and inflammation in age-related macular degeneration.

Lidianys Maria Lewis-Luján, Annette Pulcherie Iloki Lewis, Diego Emmanuel Guerrero Magaña, Clara Rosalia Alvarez Chavez, Mikhail A Osadchuk, Maxim V Trushin, Juan Carlos Galvez Ruiz, Judas Tadeo Vargas Durazo, Cinthia Jhovanna Perez Martinez, Sergio Trujillo López, Simon Bernard Iloki-Assanga.

  Age-related macular degeneration (AMD) is a multifactorial retinal neurodegenerative disease characterized by oxidative stress, chronic inflammation, retinal pigment epithelium (RPE) dysfunction, and progressive central vision loss. Marine-derived bioactive compounds from Mexican Pacific Sargassum species have emerged as promising nutraceutical candidates due to their antioxidant, anti-inflammatory, and cytoprotective properties. This narrative review critically examines the nutritional composition and pharmacologically relevant bioactive constituents of Mexican Pacific Sargassum, with emphasis on fucoxanthin, fucoidans, phlorotannins, and polyunsaturated fatty acids. Particular attention is given to their molecular mechanisms of action in AMD-related pathways, including modulation of oxidative stress, Nrf2/HO-1 signaling, NF-κB-mediated inflammation, VEGF-associated angiogenesis, mitochondrial dysfunction, and apoptosis in retinal cells. Current evidence from preclinical retinal models suggests that these compounds may exert protective effects against AMD progression through multipronged regulation of redox and inflammatory pathways. Additionally, major translational challenges related to bioavailability, extraction standardization, safety, and the absence of AMD-specific clinical trials are critically discussed. Overall, Mexican Pacific Sargassum represents a promising yet underexplored source of marine bioactives with potential applications in the development of nutraceutical strategies targeting retinal degeneration and AMD.

Keywords:  Sargassum; age-related macular degeneration; fucoidans; fucoxanthin; oxidative stress; retinal pigment epithelium

DOI:  https://doi.org/10.3389/fnut.2026.1888072
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2526200123

3D epigenomic landscape of the human retinal pigment epithelium.

Xiyuan Liu, Dongmei Tang, Jing Zhang, Tong Li, Jiaxiang Huang, Jia Qu, Yijun Ruan, Haoxi Chai, Zai-Long Chi.

  The retinal pigment epithelium (RPE) is crucial for visual function, and its dysfunction contributes to retinal diseases such as age-related macular degeneration. Despite the translational potential of iPSC-derived RPE (iPSC-RPE) in cell replacement therapy, the functional visual gains achieved to date are modest. A key challenge is that the molecular and epigenomic signatures underlying functional RPE are yet to be fully elucidated. By integrating multiomics data, we systematically benchmarked the 3D epigenomic landscapes of primary human RPE (hRPE), iPSC-RPE, and the immortalized ARPE-19 cell line. Our analysis reveals that iPSC-RPE exhibits a mixed molecular state. iPSC-RPE recapitulates hRPE-like transcription and chromatin looping, but its histone modification states remain incompletely matured, and its chromatin accessibility and higher-order chromatin organization do not fully converge to hRPE. Furthermore, we found that hRPE exhibits strong extracellular matrix (ECM) organization driven by enhancer-mediated long-range chromatin interactions and enriched RUNX1 motifs, while iPSC-RPE retains key developmental-related transcriptional signatures, marked by factors such as HAND1, OTX2, and PAX6. These findings establish a multiomics benchmark for RPE maturity, pinpoint key regulatory nodes like ECM organization and RUNX1 for therapeutic targeting, and provide a roadmap for optimizing differentiation protocols and scaffold design in retinal regenerative medicine.

Keywords:  3D epigenomic; RPE transplantation; extracellular matrix; human primary retinal pigment epithelium; iPSC-derived retinal pigment epithelium

DOI:  https://doi.org/10.1073/pnas.2526200123
Exp Eye Res. 2026 Aug 07. pii: S0014-4835(26)00345-3. [Epub ahead of print] 111189

Cellular Senescence in Posterior Segment Neovascular Diseases: A Proposed Feed-Forward Amplification Model.

Yumo Wang, Tianyi Luo, Cunzi Li, Lan Zhou, Hongzhan Lin, Ming-Ming Yang.

  Neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) continue to be significant contributors to permanent visual impairment. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has substantially improved disease management, recurrent neovascularization, persistent leakage, incomplete treatment response, subretinal fibrosis in nAMD, and fibrovascular membrane formation or tractional complications in PDR indicate that disease progression involves mechanisms beyond VEGF signaling alone. Cellular senescence-a stress-induced condition marked by persistent cell-cycle arrest, altered stress responses, and context-dependent senescence-associated secretory phenotype (SASP) activity-has been identified as a potential pathogenic amplifier in posterior-segment neovascular diseases. Chronic oxidative stress, hyperglycemia, hypoxia, metabolic dysfunction, and inflammation in the retina and choroid may induce senescence-associated or senescence-like remodeling in retinal pigment epithelial cells, Müller glia, endothelial cells, and pericytes. Nonetheless, conclusive evidence of bona fide cellular senescence in human ocular tissues remains scarce and varies markedly across cell types and disease contexts. This review integrates direct experimental evidence, marker-based observations, and inferred mechanistic insights to delineate a proposed, evidence-based senescence-associated feed-forward amplification model. In this model, chronic pathological stress may initiate or reinforce senescence-related programs, whereas SASP factors, extracellular vesicles, and immune microenvironment remodeling may further amplify angiogenic, inflammatory, vascular, and fibrotic dysfunction. Importantly, this model should be interpreted as a hypothesis-generating, non-exclusive framework rather than a fully established causal pathway. We also compare disease-specific features of nAMD and PDR, discuss methodological challenges in defining retinal senescence, and evaluate the translational potential and safety concerns of senolytics and SASP-modulating strategies as adjuncts to anti-VEGF therapy. Rather than presenting cellular senescence as a fully established causal driver, this review frames senescence-associated remodeling as a context-dependent, evidence-stratified amplifying component within this proposed feed-forward framework.

Keywords:  Cellular Senescence; Feed-forward Amplification Model; Neovascular AMD (nAMD); Proliferative Diabetic Retinopathy (PDR); Senescence-Associated Secretory Phenotype (SASP)

DOI:  https://doi.org/10.1016/j.exer.2026.111189
Cell Rep Med. 2026 Aug 03. pii: S2666-3791(26)00380-0. [Epub ahead of print] 102963

EGFR inhibition promotes functional engraftment and graft survival via donor-derived CHI3L1 in fetal RPE suspension transplantation.

Xiying Mao, Wenjie Yin, Miao Xu, Zixuan Niu, Dingan Zhong, Benchen Ye, Siqi Xu, Yan Gao, Wenbo Zhang, Qiang Chen, Guokai Chen, Ning-Yi Shao, Peng Xie, Minjun Ji, Guoping Fan, Qinghuai Liu, Songtao Yuan.

  Numerous clinical trials have highlighted the translational potential of retinal pigment epithelial (RPE) cell transplantation in retinal degeneration (RD). However, an unsolved challenge remains in addressing chronic graft dysfunction, primarily due to poor integration and cell loss. Here, we perform a single-cell transcriptomic comparison between grafted RPE cells and host RPE. Our analysis identifies EGFR expression in donor fetal RPE cells as a significant obstacle to functional integration. Through multimodal imaging and spatial transcriptomics, we demonstrate that EGFR inhibition (EGFRi) facilitates effective engraftment of fetal RPE cell suspension, leading to the functional restoration of the outer blood-retinal barrier, and restrains neurodegeneration in preclinical RD models. This effect is mechanistically linked to graft reepithelialization via the activation of intrinsic CHI3L1-IL13RA2 signaling in EGFRi-treated donor cells. Moreover, EGFRi-induced CHI3L1 secretion contributes to immunosuppression that complements anti-lymphocytic therapy, thereby extending graft survival. Thus, repurposing Food and Drug Administration (FDA)-approved EGFR inhibitor offers a safe and cost-effective approach to advancing fetal RPE suspension transplantation into clinical practice.

Keywords:  EGFR inhibition; RPE suspension transplantation; fetal RPE; functional integration; immunosuppression; retinal degeneration

DOI:  https://doi.org/10.1016/j.xcrm.2026.102963
J Oleo Sci. 2026 ;75(8): 921-932

N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity.

Zhixing Cai, Yue Chen, Lili Chen, Danyang Zhu.

   BACKGROUND: Palmitic acid (PA)-driven lipotoxicity in skeletal muscle is associated with excessive reactive oxygen species (ROS) and disturbed mitochondrial dynamics. This study aimed to characterize PA-induced alterations in oxidative status and fusion-fission balance in C2C12 skeletal muscle cells and to test whether N-acetylcysteine (NAC), dichloroacetate (DCA), or metformin mitigate these changes.
METHODS: Differentiated C2C12 myotubes were exposed to PA under conditions detailed in the Methods. Intracellular ROS was quantified, antioxidant defenses were assessed by activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), and mitochondrial dynamics were evaluated by expression of the fusion protein mitofusin 1 (MFN1) and the fission protein dynamin-related protein 1 (DRP1), together with morphological assessment of mitochondrial fragmentation.
RESULTS: PA exposure increased ROS and was accompanied by decreases in CAT, GPx, and SOD activities. PA shifted mitochondrial dynamics toward fission, with reduced MFN1, elevated DRP1, and increased mitochondrial fragmentation. Co-treatment with NAC, DCA, or metformin attenuated PA-induced ROS accumulation, improved antioxidant enzyme activities relative to PA alone, and partially normalized MFN1 and DRP1 expression, with reduced fragmentation.
CONCLUSIONS: In an in vitro C2C12 model, PA-induced lipotoxicity is associated with oxidative stress and a fusion-fission imbalance favoring mitochondrial fragmentation. NAC, DCA, and metformin mitigate these alterations and help preserve mitochondrial homeostasis. These findings support targeting oxidative stress and mitochondrial dynamics as a potential approach to counteract mitochondrial dysfunction under lipotoxic conditions.

Keywords:  insulin resistance; mitochondrial dysfunction; oxidative stress; palmitic acid

DOI:  https://doi.org/10.5650/jos.ess25268