bims-mideyd 2025-08-03 papers

Commun Biol. 2025 Jul 29. 8(1): 1118

Endoplasmic reticulum-mitochondria coupling prompts ZBP1-mediated RPE cell PANoptosis in age-related macular degeneration.

Ao Zhang, Ting-Ting Wei, Honglin Yin, Cheng-Ye Tan, Cheng Han, Yong Yao, Lingpeng Zhu.

Age-related macular degeneration (AMD) is the leading cause of central vision impairment among the elderly. Geographic atrophy is a defining characteristic of AMD, but the detailed mechanism for massive loss of retinal pigment epithelium (RPE) cells is not fully understood. In this study, we found that Z-DNA binding protein 1 (ZBP1), a sensor for dsDNA, is able to induce RPE cell PANoptosis. Silencing ZBP1 efficiently alleviates RPE degeneration and AMD symptoms. Mechanistically, mitochondrial permeability transition pore (mPTP) opening stimulated by Ca2+ overload can trigger the releasing of mtDNA, which leads to ZBP1 activation and PANoptosis. Importantly, our findings reveal a significant role of aberrant formation of mitochondria-associated ER membranes (MAMs) in AMD. MAMs act as conduits for transferring Ca2+ from the ER to mitochondria through the VDAC1/GRP75/IP3R1 complex. Furthermore, our results indicate that GRP75 O-GlcNAcylation is involved in MAM formation. Genetic suppression of GRP75 attenuates PANoptosis and AMD progression. In summary, our study sheds light on the intricate organelle interplay underlying AMD and presents insights into potential avenues for AMD intervention.

DOI: https://doi.org/10.1038/s42003-025-08565-z

Invest Ophthalmol Vis Sci. 2025 Jul 01. 66(9): 67

Complement C3 Activation in the Human Retinal Pigment Epithelium.

Juliane Schikora, Antonia Nickel, Jasmin Bergert, Rike Hähnel, Aaron Dort, Ben C King, Stella Y Schayan-Araghi, Pratiti Banerjee, Hannah N Wolf, Helen May-Simera, Diana Pauly.

Purpose: Epithelial maturation is essential for the specificity and functionality of retinal pigment epithelial (RPE) cell models. This study investigates how different maturation conditions shape RPE characteristics and cellular complement biology in two commonly used in vitro models: ARPE-19 and induced pluripotent stem cell-derived RPE (iPSC-RPE).
Methods: ARPE-19 and iPSC-RPE cells were cultured under low maturation (LM) or high maturation (HM) conditions. Phenotype, RPE marker expression, and functional properties were assessed, and expression of local complement components was analyzed at the transcript, protein, and secretion levels. Intracellular complement C3 processing was characterized using epitope-specific antibodies.
Results: HM conditions enhanced epithelial features in both models, with HM iPSC-RPE displaying enhanced apical localization of RPE markers, polarity, reduced cilia length, and higher transepithelial resistance. Expression and secretion of complement components C3, FB, FH/FHL-1, and FI, as well as FH staining patterns, varied with maturation condition. HM iPSC-RPE secreted increased levels of C3a, C3(H2O), and iC3b, whereas LM cells retained C3 fragments intracellularly. Western blotting and immunostaining revealed maturation-dependent C3 fragment profiles, with apical localization of C3 and intracellular presence of the intact C3 β chain in HM iPSC-RPE, while C3 fragments were present in LM and ARPE-19 cells.
Conclusions: HM iPSC-RPE cells most closely mimic native RPE features and provide a robust model for in vitro studies. RPE cells exhibit cell-autonomous complement production and maturation-dependent C3 activation profiles, providing a foundation for future studies on C3 functionality in RPE homeostasis and retinal degeneration.

DOI: https://doi.org/10.1167/iovs.66.9.67

Mol Aspects Med. 2025 Jul 28. pii: S0098-2997(25)00053-6. [Epub ahead of print]105 101389

Unveiling the P2X7 receptor: Exploring its mechanisms, pathogenic role in ocular diseases, and emerging therapeutic potential.

Kai-Yang Chen, Hoi-Chun Chan, Chi-Ming Chan.

Purinergic signaling, mediated by extracellular ATP (eATP) and P2 receptors, plays a vital role in physiological and pathological processes. The P2X7 receptor (P2X7R), a ligand-gated cation channel, is crucial in inflammation, cell death, and immune responses. Widely expressed in retinal cells, P2X7R contributes to visual function regulation and retinal degeneration. This review explores P2X7R involvement in retinal diseases, including age-related macular degeneration (AMD), Behçet's disease (BD), diabetic retinopathy (DR), glaucoma, retinitis pigmentosa (RP), uveitis, Stargardt's disease (STGD), and toxoplasmosis. P2X7R activation drives inflammation, oxidative stress, apoptosis, and immune dysregulation. For instance, it contributes to RPE degeneration in AMD, vascular proliferation in DR, neuroinflammation in glaucoma, and photoreceptor loss in RP. In uveitis, P2X7R enhances Th1 and Th17 responses. Targeting P2X7R with antagonists or modulators holds therapeutic potential, offering strategies to preserve retinal function and prevent vision loss in these debilitating diseases.

Keywords: Microglia; P2X7; Photoreceptors; Retinopathy; Sodium iodate

DOI: https://doi.org/10.1016/j.mam.2025.101389