bims-mideyd 2026-07-19 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–07–19
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Kinsenoside alleviates retinal pigment epithelium cell injury in age-related macular degeneration-like retinal injury through exosome-associated modulation of JNK/MAPK signaling.
RGR-opsin maintains cellular homeostasis by ameliorating the proteotoxicity of its exon-skipping splice variant.
Study on retinal pharmacokinetic characteristics and precision drug administration strategy in patients with fundus diseases.
Personalized Pathogenicity Assessment of RPE65 Gene Mutations Using Patient-Specific hiPSC-Derived Retinal Pigment Epithelium Model.
Melatonin improves mitochondrial function and redox balance in human cartilage endplate-derived stem cells.
Soft matrix promotes ciliogenesis in human retinal pigment epithelial cells.
Mitochondrial preservation underlies the antioxidant activity of nanoceria particles in light-induced retinal degeneration.

Int Immunopharmacol. 2026 Jul 17. pii: S1567-5769(26)00985-9. [Epub ahead of print]186 117139

Kinsenoside alleviates retinal pigment epithelium cell injury in age-related macular degeneration-like retinal injury through exosome-associated modulation of JNK/MAPK signaling.

Yue Bai, Maosong Xie, Yihua Yao, Biting Zhou, Yihua Zhu.

   BACKGROUND: Dry age-related macular degeneration (AMD) is driven largely by retinal pigment epithelium (RPE) cell injury. Kinsenoside (KN) exhibits protective activity on RPE cells, but the direct effect on dry AMD and underlying molecular mechanisms remain unclear.
OBJECTIVE: This study aimed to investigate the protective effects of KN against RPE cell injury and dysfunction in dry AMD and to elucidate its regulatory mechanisms.
METHODS: An A2E- and blue light-induced ARPE-19 cell injury model and a blue light-induced AMD-like retinal injury mouse model were established. RPE cytotoxicity, apoptosis, senescence, inflammation, and melanogenesis-associated marker expression were evaluated. MAPK signaling was analyzed by Western blotting, and mechanistic analyses were performed using a JNK inhibitor, molecular docking analysis, an in vitro JNK enzymatic activity assay, exosome characterization, and exosome functional assays.
RESULTS: KN treatment significantly attenuated cytotoxicity, apoptosis, cellular senescence, inflammatory responses, and melanogenesis-associated marker alterations in AMD-like ARPE-19 cells. In vivo, KN reduced drusen-like deposition, improved retinal structural integrity, and partially restored outer nuclear layer thickness while suppressing senescence and inflammation. Mechanistically, KN preferentially attenuated pathological JNK activation under the examined conditions and reduced JNK enzymatic activity in vitro. Pharmacological JNK inhibition phenocopied the protective effects of KN with no additive benefit, indicating pathway convergence. Exosome inhibition, transfer, and depletion experiments supported the contribution of exosome-associated signaling to KN-mediated cytoprotection.
CONCLUSION: These findings suggest that KN alleviates RPE cell injury under AMD-like stress, at least partly through exosome-associated modulation of JNK/MAPK signaling.

Keywords:  Dry age-related macular degeneration; Exosomes; Kinsenoside; MAPK/JNK signaling; Retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.intimp.2026.117139
Exp Eye Res. 2026 Jul 17. pii: S0014-4835(26)00281-2. [Epub ahead of print] 111125

RGR-opsin maintains cellular homeostasis by ameliorating the proteotoxicity of its exon-skipping splice variant.

Wenqian Chen, Li Zhu, Chi Ren, Jiarui Li, Shuting Liang, Wenzhen Yu, Zhiming Liu, Wei Du, Huichao Yan, Yue Wen, Henry K W Fong, Mingwei Zhao.

   PURPOSE: One of the alternative splicing variants of retinal G protein-coupled receptor (RGR), RGR-d, is recognized as a misfolded protein. With or without inhibition of the proteasome system, RGR-d has a cytotoxic effect on retinal pigment epithelium (RPE) cells. RGR-d mutant mice exhibit age-related macular degeneration-like pathologic changes. However, humans with RGR-d likely express both wild-type and splice variant forms. In this study, we investigate the protective influence of the co-expression of RGR and RGR-d protein in RPE cells.
METHODS: ARPE-19 cells overexpressing both RGR and RGR-d were treated with or without MG132. The protein-protein interaction, ubiquitination, endoplasmic reticulum (ER) stress, autophagy flux, and subcellular localization were explored. Aged RGR-d mice were subjected to ocular examination.
RESULTS: We confirm that RGR binds RGR-d in RPE cells and decreases the polyubiquitin of RGR-d. Formation of the RGR/RGR-d complex could assist RGR-d in correctly folding on the endoplasmic reticulum (ER), and ameliorate ER stress and autophagy inhibition that were induced by misfolded RGR-d protein. The complexes highly colocalize with Golgi apparatus and maintain its typical morphology, avoiding degradation by lysosomes. We observed that RGR-d mice exhibited AMD-like subretinal hyper-reflective deposits on fundus examination.
CONCLUSIONS: We have identified a fundamental mechanism in which RGR-opsin binds its splice variant, RGR-d, to form a protective complex that alleviates cytotoxicity to RPE. This discovery is significant as it reveals a previously unknown endogenous defense against proteotoxicity in the retina. Targeting the RGR-d may represent a novel and highly promising intervention for the protein-misfolding pathology of dry age-related macular degeneration.

Keywords:  Age-related macular degeneration; Autophagy; Endoplasmic reticulum stress; Opsin; Retinal G protein-coupled receptor; Splice variant

DOI:  https://doi.org/10.1016/j.exer.2026.111125
Pak J Pharm Sci. 2026 Sep;39(9): 2825-2836

Study on retinal pharmacokinetic characteristics and precision drug administration strategy in patients with fundus diseases.

Liang Fu, Lei Huang, Ruxue Guo, Li Wu, Xiang Zeng, Zhihe Fu.

   BACKGROUND: Fundus diseases are major causes of irreversible visual impairment. Retinal pharmacokinetic behavior may differ between diabetic retinopathy (DR) and age-related macular degeneration (AMD), but disease-specific dosing principles remain insufficiently defined.
OBJECTIVES: Disease-stratified retinal pharmacokinetic characteristics were evaluated, and a precision drug administration strategy for patients with fundus diseases was developed.
METHODS: Blood-retinal barrier (BRB) cell models, retinal organoids, retinal pigment epithelium (RPE) models, optical coherence tomography (OCT), serum biomarkers and clinical records were integrated. A retrospective, controlled clinical analysis was performed in patients with DR or AMD, in accordance with ethics approval No. 20240923.
RESULTS: DR was characterized by greater barrier permeability and transporter-related retention, whereas AMD was characterized by lipid-associated RPE dysfunction and restricted trans-retinal penetration. The DR model predicted retinal peak concentration with R2 = 0.89, and the AMD model predicted drug half-life with 86% accuracy. Precision administration was associated with reduced injection frequency in DR and AMD and improved anatomical and visual outcomes.
CONCLUSION: Disease-specific retinal pharmacokinetic differences support individualized dosing strategies for fundus diseases. The proposed platform provides a practical framework for precision anti-VEGF therapy and targeted retinal drug delivery.

Keywords:   Blood-retinal barrier ; Fundus diseases ; Nano-drug delivery system ; Precision drug administration ; Retinal pharmacokinetics

DOI:  https://doi.org/10.36721/PJPS.2026.39.9.263.1
Int J Mol Sci. 2026 Jun 23. pii: 5643. [Epub ahead of print]27(13):

Personalized Pathogenicity Assessment of RPE65 Gene Mutations Using Patient-Specific hiPSC-Derived Retinal Pigment Epithelium Model.

Ke Ye, Suai Zhang, Ping Xu, Xiaojing Song, Yuan Wang, Xiufeng Zhong.

  RPE65, an isomerohydrolase expressed in retinal pigment epithelium (RPE), is critical for the visual cycle. More than 115 missense variants of the RPE65 gene have been associated with Leber's congenital amaurosis (LCA), a severe childhood retinal dystrophy. Due to high genetic heterogeneity, the variant-specific pathogenic mechanisms remain largely uncharacterized. In this study we focus on an LCA patient carrying compound heterozygous RPE65 variants (c.200T > G, c.430T > C), aiming to dissect the mechanistic/functional basis of mutated protein-driven retinal degeneration and evaluate gene therapy-mediated restoration using patient-specific hiPSCs-RPE (iRPE). Transient overexpression of wild-type/mutant RPE65 in HEK293T cells showed both variants markedly destabilize the RPE65 protein through the autophagosome-lysosome degradation pathway and its isomerohydrolase activity required for the retinoid visual cycle. We further established a patient-specific iRPE platform suitable for enzymatic activity analysis. Characterization of patient-specific iRPE cells revealed those compound heterozygous variants did not compromise iRPE morphology, most gene expression, or core canonical physiological features of iRPE. However, they significantly downregulate endogenous RPE65 protein abundance and dampen enzymatic function. Subsequently, we delivered RPE65 via adeno-associated viral (AAV) vectors driven by either the ubiquitous CMV promoter or RPE-specific VMD2 promoter into patient iRPE to validate therapeutic potency, and verified that exogenous RPE65 supplementation effectively restores deficient isomerohydrolase activity in this disease model. Collectively, this work elucidates the variant-specific pathogenesis of RPE65-associated LCA and preliminarily assesses the efficacy of gene augmentation, providing preclinical experimental evidence to support the referral of this patient for clinical RPE65 gene replacement therapy.

Keywords:  Leber’s congenital amaurosis; RPE65; gene therapy; retinal pigment epithelium; stem cells; vitamin A cycle

DOI:  https://doi.org/10.3390/ijms27135643
Cytotechnology. 2026 Aug;78(4): 160

Melatonin improves mitochondrial function and redox balance in human cartilage endplate-derived stem cells.

Pingfan Mo, Rongchun Chen, Linbo Sun, Yunsheng Chen, Jun Xiong, Yaohong Wu, Canhua Xu.

  Mitochondrial oxidative stress is an important factor affecting the biological activity of stem cells under degenerative microenvironments. Cartilage endplate-derived stem cells (CESCs) are considered to participate in intervertebral disc homeostasis; however, their mitochondrial redox status under degeneration-related conditions remains incompletely characterized. In this study, human CESCs were isolated from patients with different degrees of intervertebral disc degeneration and used as an in vitro model to investigate mitochondrial oxidative stress. For intervention experiments, CESCs were treated with 100 µM melatonin for 24 h. Intracellular reactive oxygen species and mitochondrial superoxide were assessed using DCFH-DA and MitoSO™ Red, respectively. Mitochondrial membrane potential, ATP production, catalase and superoxide dismutase activities, and mitochondrial ultrastructure were evaluated. SIRT3 mRNA and protein expression were examined by quantitative real-time PCR and western blotting, and siRNA-mediated SIRT3 knockdown was used to explore its potential involvement in mitochondrial regulation. CESCs derived from advanced degeneration exhibited increased oxidative stress, decreased mitochondrial membrane potential, reduced ATP production, lower antioxidant enzyme activity, and greater mitochondrial ultrastructural damage. Melatonin treatment reduced intracellular ROS and mitochondrial superoxide accumulation and improved mitochondrial function. SIRT3 knockdown reduced SIRT3 mRNA and protein expression and partially attenuated the protective effects associated with melatonin. Melatonin increased SIRT3 mRNA expression, while SIRT3 protein expression was higher in the melatonin-treated group than in the SIRT3-siRNA group. These findings suggest that melatonin improves mitochondrial redox balance and mitochondrial function in human CESCs and that SIRT3 may participate in this regulatory process. The present study provides experimental evidence supporting a potential role for melatonin in modulating mitochondrial oxidative stress under degeneration-associated conditions.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-026-01025-4.

Keywords:  Cartilage endplate; Intervertebral disc degeneration; Melatonin; Mitochondrial dysfunction; Oxidative stress; SIRT3

DOI:  https://doi.org/10.1007/s10616-026-01025-4
Sci Rep. 2026 07 13. pii: 21859. [Epub ahead of print]16(1):

Soft matrix promotes ciliogenesis in human retinal pigment epithelial cells.

Rida Zahra, Natalie Munding, Katrin Domsch, Hannah Braun-Lee, Camila García-Navarrete, Motomu Tanaka, Gislene Pereira.

  The primary cilium (PC) is a microtubule-based mechanosensory organelle involved in signal transduction. Although the signaling functions of PC have been well studied, its interaction with the cell´s mechanical environment remains unclear. Here, we used polyacrylamide hydrogels to investigate how extracellular matrix (ECM) stiffness influences ciliogenesis in human retinal pigment epithelial (RPE1) cells. We found that a soft hydrogel (1 kPa) induces cilia formation and elongation in RPE1 cells independent of serum starvation, a classical in vitro method to promote ciliogenesis. Transcriptome analysis of serum-fed RPE1 cells on soft matrix revealed cell cycle exit and alterations in ECM and cytoskeletal gene expression that favor ciliogenesis. Moreover, we observed that despite being very long, cilia formed on a soft substrate are functional, as they transduce Sonic hedgehog signal normally. Transcriptome and microscopy analysis of two cilia-inducing conditions (soft substrate and serum starvation) revealed upregulation of cilia-related genes and downregulation of proliferation markers on both conditions. Autophagy genes were more enriched in serum-starved cells, whereas upregulation of ECM genes and downregulation of actin-related genes were more pronounced on soft matrix. Our study demonstrates that PC biogenesis can be mechanically induced in RPE1 cells on soft substrates independent of external biochemical cues.

Keywords:  Atg5; Autophagy; Ciliogenesis; Matrix stiffness; Polyacrylamide hydrogels; Primary cilium; RPE1; Serum starvation; Soft matrix; Transcriptome

DOI:  https://doi.org/10.1038/s41598-026-61461-2
Nanomedicine. 2026 Jul 15. pii: S1549-9634(26)00096-1. [Epub ahead of print] 102995

Mitochondrial preservation underlies the antioxidant activity of nanoceria particles in light-induced retinal degeneration.

Darin Zerti, Luigi Donato, Ignacio Babiloni Chust, Giulia Carozza, Omar Giangiulio, Marta Stefanini, Enver Faella, Marco Feligioni, Jacopo Di Gregorio, Vincenzo Flati, Matthias Carl, Lucia Poggi, Rosalia D'Angelo, Maurizio Passacantando, Rita Maccarone.

  Age-related Macular Degeneration (AMD), the leading cause of blindness worldwide, is a multifactorial disease with mitochondrial dysfunction recognized as an early pathogenic event. In our preclinical studies, we demonstrated that a single Cerium-Oxide Nanoparticles (CeO2-NPs) intravitreal injection in a light-induced degeneration model, was able to counteract the retinal degeneration. Our aim was to investigate whether neuroprotection activity could be correlated with mitochondrial morpho-functional preservation. Bulk transcriptomic profiling of whole retinal tissue revealed that light-induced retinal injury was associated with suppression of mitochondrial-related gene networks, including components of the electron transport chain and regulators of mitochondrial dynamics, whereas CeO2-NPs treatment restored the expression of antioxidant and mitochondrial biogenesis-related genes. Ultrastructural analysis by electron microscopy showed preservation of Retinal Pigmented Epithelial mitochondria's morphology and by high-resolution crystallographic analysis confirmed the intracellular localization of CeO2-NPs in proximity to mitochondria. Furthermore, Western blot analysis demonstrated that CeO2-NPs maintained mitophagy markers at basal levels, preventing excessive activation of mitochondrial quality-control pathways. Together, these findings support mitochondrial preservation as a key mechanism underlying nanoceria-mediated retinal neuroprotection and highlight CeO2-NPs as promising candidates for maintaining retinal homeostasis in AMD.

Keywords:  Age-related macular degeneration; Cerium oxide nanoparticles; Mitochondria; Retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.nano.2026.102995