bims-mideyd 2025-11-16 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2025–11–16
six papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

FOXO4 Facilitates Diabetic Retinopathy by Mediating KLF7 Transcription and Affecting the TLR4/MyD88/NF-κB Pathway.
Dysregulated DNA Methylation in Abca4-/- Retinal Pigment Epithelium: Insights into Early Stage of Stargardt Disease.
N-acetyl-l-cysteine ethyl ester (NACET) induces the transcription factor NRF2 and prevents retinal aging and diabetic retinopathy.
The roles of glycerophospholipids in the aging retina and age-related macular degeneration.
Tricin inhibits the migration of human retinal pigment epithelium cells by suppressing the RUNX2-CYP1A1 axis and STAT3 pathway.
Identification and validation of key mitophagy-related biomarkers in the pathogenesis of proliferative diabetic retinopathy.

Appl Biochem Biotechnol. 2025 Nov 13.

FOXO4 Facilitates Diabetic Retinopathy by Mediating KLF7 Transcription and Affecting the TLR4/MyD88/NF-κB Pathway.

Wenwen Yang, Guangjun Xu, Dengxue Wang.

   BACKGROUND: Diabetic retinopathy (DR) affects vision and can even cause blindness. Kruppel-like factor 7 (KLF7) takes part in high-glucose (HG)-prompted retinal pigment epithelial cell (RPE) apoptosis in vitro, the molecular mechanisms of KLF7-mediated DR pathogenesis are poorly studied.
METHODS: HG-challenged RPEs were used as a model for DR in vitro. Cell viability, proliferation, apoptosis, and inflammation were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, 5-ethynyl-2'-deoxyuridine, flow cytometry, and TUNEL assays. Oxidative stress damage was determined by detection of ROS and MDA. The interaction between KLF7 and forkhead box protein O4 (FOXO4) was estimated by chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays. The toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway was assessed by western blot and the NF-κB inhibitor BAY 11-7085.
RESULTS: HG induced up-regulation of KLF7 in RPEs, and KLF7 silencing weakened HG-induced RPE apoptosis, inflammation, and oxidative stress damage. FOXO4 activated the transcription of KLF7, and FOXO4 silencing demonstrated the same function as KLF7 knockdown in HG-challenged RPEs. Moreover, KLF7 down-regulation reversed FOXO4 overexpression-mediated promoting effect on HG-induced RPE injury. Interestingly, FOXO4 activated the TLR4/MyD88/NF-κB pathway by KLF7, and BAY 11-7085 overturned KLF7 elevation-mediated effects on HG-induced RPE injury.
CONCLUSION: FOXO4 participated in HG-induced RPE injury via activation of the TLR4/MYD88/NF-κB pathway by enhancing the transcription of KLF7, supporting that FOXO4 and KLF7 as potential targets for DR treatment.

Keywords:  Diabetic retinopathy; FOXO4; HG; KLF7; Oxidative stress

DOI:  https://doi.org/10.1007/s12010-025-05466-z
Int J Mol Sci. 2025 Nov 05. pii: 10742. [Epub ahead of print]26(21):

Dysregulated DNA Methylation in Abca4-/- Retinal Pigment Epithelium: Insights into Early Stage of Stargardt Disease.

Arpita Dave, Anela Tosevska, Marco Morselli, Emily Tom, Matteo Pellegrini, Dorota Skowronska-Krawczyk, Roxana A Radu.

  Stargardt disease (STGD1), the most common inherited juvenile macular degeneration, is caused by biallelic mutations in the ABCA4 gene. Currently, there is no approved treatment. In this study, we investigated early-stage epigenomic changes in the retinal pigment epithelium (RPE) of Abca4-/- mice, a well-established model of STGD1. Reduced representation bisulfite sequencing (RRBS) revealed hypermethylation of gene regions associated with disease-related pathways, implicating methyl-CpG-binding protein 2 (MeCP2) and RE1-silencing transcription factor (REST) as potential regulators. Notably, DNA methylation of a subset of genes preceded their transcriptional change and disease phenotypes in Abca4-/- RPE. Together with the detected age-dependent increase in MeCP2 levels in Abca4-/- RPE, these findings suggest that early DNA methylation changes may contribute to RPE dysfunction and eventual cell loss in STGD1.

Keywords:  DNA methylation; methyl-CpG-binding protein 2; recessive Stargardt disease; reduced representation bisulfite sequencing; retinal pigment epithelium

DOI:  https://doi.org/10.3390/ijms262110742
Redox Biol. 2025 Nov 03. pii: S2213-2317(25)00427-6. [Epub ahead of print]88 103914

N-acetyl-l-cysteine ethyl ester (NACET) induces the transcription factor NRF2 and prevents retinal aging and diabetic retinopathy.

Giulia Realini, Rosario Amato, Mahdi Rasa, Roberto Ceccatelli, Angela Cannavale, Laura Bottoni, Federico Marchini, Alberto Minetti, Daniela Giustarini, Alessio Canovai, Alberto Melecchi, Ines Elia, Anna Krepelova, Francesco Annunziata, Maurizio Cammalleri, Ranieri Rossi, Gian Marco Tosi, Maurizio Orlandini, Mario Chiariello, Francesco Neri, Massimo Dal Monte, Federico Galvagni.

  Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are leading causes of visual impairment in older people, with oxidative stress playing a central role in the development of these diseases. In this study, we showed that N-acetylcysteine ethyl ester (NACET) not only increases intracellular cysteine and glutathione levels, but also strongly stimulates the expression and activity of the transcription factor NRF2, a master regulator of oxidative stress response, in RPE cells. Using RNA interference, mass spectrometry and mutagenesis of the NRF2 regulator KEAP1, we identified direct cysteinylation of the sensor residues Cys226 and Cys613 on KEAP1 as the molecular mechanism underlying NRF2 activation after NACET treatment. Furthermore, we demonstrated that oral administration of NACET induces NRF2 activity in the retina in vivo, attenuates retinal aging hallmarks, and prevents diabetes-induced retinal neurodegeneration in mouse models. These results position NACET as a promising therapeutic candidate for age- and oxidative stress-related retinal diseases such as AMD and DR.

Keywords:  Age-related macular degeneration (AMD); Cysteine (Cys); Cystine (Cyss); Diabetic retinopathy (DR); Kelch-like ECH-Associated protein 1 (KEAP1); N-Acetylcysteine ethyl ester (NACET); NF-E2-related factor 2 (NRF2); Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2025.103914
Graefes Arch Clin Exp Ophthalmol. 2025 Nov 13.

The roles of glycerophospholipids in the aging retina and age-related macular degeneration.

Yingxin Yu, Yun Sun, Tantai Zhao.

  Glycerophospholipids (GPs) are integral constituents of cellular membranes, and play a crucial role in the regulation of lipid metabolism homeostasis and physiological conditions. However, pathological alterations associated with aging, such as variations in plasma GP concentrations, disruptions in intercellular GP transport, and local accumulation of excessive GPs, have been observed. These changes induce irreversible cellular degeneration, ultimately leading to tissue damage in organs such as the brain and retina. A growing body of evidences has demonstrated that GPs play significant roles in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Similarly, GPs have been implicated in the pathogenesis and progression of age-related macular degeneration (AMD), a degenerative condition affecting the choroid and retinal layers of the eye. Understanding the homeostasis of GP metabolism in the aging retina and in AMD is essential for elucidating the pathogenic processes involved in AMD. In this review, we present a comprehensive overview of the mechanisms of GPs in the aging retina and their correlation with degenerative processes associated with AMD. KEY MESSAGES: What is known Metabolic dysregulation of glycerophospholipids (GPs) plays vital roles in age-related macular degeneration (AMD) and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Patients with age-related neurological disorders exhibit a significantly higher risk of developing AMD compared to healthy individuals, potentially due to shared pathological mechanisms, including mitochondrial metabolic disturbance, chronic inflammation and autophagy dysfunction. What is new The interconnection between multiple GP species and their metabolites has been established to delineate complex pathogenic mechanisms underlying the aging retina and AMD, including cell senescence, autophagy and apoptosis, oxidative stress, inflammation, vascular abnormalities. GPs may serve as potential therapeutic targets to prevent or delay the progression of AMD.

Keywords:  Age-related macular degeneration; Aging; Glycerophospholipid metabolism; Glycerophospholipids; Retina

DOI:  https://doi.org/10.1007/s00417-025-07011-4
Int J Med Sci. 2025 ;22(16): 4344-4352

Tricin inhibits the migration of human retinal pigment epithelium cells by suppressing the RUNX2-CYP1A1 axis and STAT3 pathway.

Wei-Yang Lu, I-Chia Liang, Yi-Hsien Hsieh, Kai Wang, Chia-Yi Lee, Nuo-Yi Yu, Shun-Fa Yang, Hsiang-Wen Chien.

  Proliferative vitreoretinopathy (PVR) is a retinal disorder characterized by abnormal growth and migration of retinal pigment epithelium (RPE) cells, leading to impaired visual acuity. Tricin is a naturally occurring flavone known to inhibit the migration of various cancer cell types. Therefore, the aim of this study was to investigate the potential inhibitory effects of tricin on the migration of ARPE-19 cells. In this study, tricin treatment significantly reduced the migratory and invasive abilities of ARPE-19 cells in the Boyden chamber assays. RNA sequencing identified cytochrome P450 1A1 (CYP1A1) as the most significantly downregulated gene following tricin treatment. Real-time PCR confirmed a reduction in CYP1A1 mRNA levels, while Western blot analysis demonstrated a concentration-dependent decrease in CYP1A1 protein expression. Moreover, siRNA-mediated knockdown of CYP1A1 resulted in decreased mRNA expression levels, accompanied by reduced cell migration. Tricin treatment also attenuated RUNX2 transcription factor levels and phosphorylation of STAT3. Co-treatment with tricin and colivelin (a STAT3 activator) led to increased CYP1A1 expression and enhanced cell migration, suggesting a regulatory role of the STAT3 pathway in tricin-mediated effects. In conclusion, tricin inhibits the migration of ARPE-19 cells by downregulating CYP1A1 and RUNX2 expression through suppression of the STAT3 signaling pathway. These findings suggest that tricin holds potential as a therapeutic candidate for preventing or limiting the progression of PVR.

Keywords:  CYP1A1; RUNX2; STAT3; proliferative vitreoretinopathy; retinal pigment epithelium; tricin

DOI:  https://doi.org/10.7150/ijms.122814
Front Endocrinol (Lausanne). 2025 ;16 1652898

Identification and validation of key mitophagy-related biomarkers in the pathogenesis of proliferative diabetic retinopathy.

Yifan Liu, Ye Zhou, Jie Chen, Jiahui Jin, Xueying Wang, Xi Wang, Jieping Zhang, Jiao Li, Junfang Zhang, Ling Zhu, Guo-Tong Xu, Yanlong Bi, Qingjian Ou, Caixia Jin.

   Introduction: Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus, and proliferative diabetic retinopathy (PDR) represents its advanced stage. The etiology of PDR is complex. Mitophagy, the selective degradation of dysfunctional mitochondria, is crucial for cellular homeostasis and has been implicated in PDR pathogenesis. However, its specific mechanisms require further investigation.
Materials and methods: Gene Expression Omnibu (GEO) datasets (GSE102485, GSE60436) were analyzed in R software to identify differentially expressed mitophagy-related genes (DEMRGs). A PDR diagnostic model was constructed by gene ontology (GO) enrichment analysis, genome enrichment analysis (GSEA), and other relevant methods. Immune infiltration was also performed to analyze the changes in immune cells. Finally, the retinal pigment epithelial cell line (ARPE-19) was incubated with high glucose (HG) to simulate a DR model in vitro, hub-gene expression and mitophagy were assessed by qRT-PCR, Western blotting, and immunofluorescence microscopy (IF).
Results: Eight DEMRGs were identified enabling construction of a PDR diagnostic model and prioritization of two hub genes (CASP8 and COL1A1). Finally, qRT-PCR, Western blotting, and IF were performed to provide preliminary validation of the PDR model and HG stimulation increased mitochondria-lysosome colocalization as well as enhanced the expression of mitophagy-related proteins.
Conclusion: Integrated bioinformatics and experimental validation suggest that mitophagy contributes to PDR pathogenesis. Five DEMRGs showed up-regulated and immune cell infiltration that may affect the occurrence and PDR development by regulating mitophagy. These findings provide candidate biomarkers and mechanistic insight into PDR.

Keywords:  CASP8; COL1A1; differentially expressed genes; mitophagy; proliferative diabetic retinopathy

DOI:  https://doi.org/10.3389/fendo.2025.1652898