bims-mideyd 2026-02-22 papers

Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2511926123

DAPL1 restrains RPE PANoptosis in experimental AMD by inhibiting GRP75-mediated mitochondria-associated endoplasmic reticulum membranes.

Yan Li, Meiyu Jing, Wanxiao Wang, Wanzhen Lin, Yingxin Zhang, Tianyin Nie, Pingping Liu, Wan-Ni Lu, Yu Chen, J Fielding Hejtmancik, Qinxiang Zheng, Ling Hou, Xiaoyin Ma.

Retinal pigment epithelium (RPE) cell damage is a critical factor of age-related macular degeneration (AMD), the leading cause of blindness among the aged population. This study focuses on the AMD susceptible gene, Death associated protein like 1 (DAPL1), and provides insights with significant therapeutic implications. DAPL1-deficient mice exhibit dry AMD-like pathological features, a phenomenon whose mechanisms have remained largely unknown. Here, we reveal that DAPL1 deficiency promotes the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to cause mitochondrial Ca2+ overload and dysfunction, which triggers the activation of inflammasomes, leading RPE cells to RIPK1-mediated PANoptosis, an inflammatory programmed cell death, in an experimental dry AMD (dAMD) mouse model. Knockdown of Ripk1 in the Dapl1-/- mice RPE inhibits RPE cell PANoptosis and ameliorates the severity of dAMD pathological features. Conversely, overexpression of DAPL1 inhibits MAM formation and protects RPE cells from PANoptosis in the model. Mechanistically, DAPL1 suppresses MAM formation by downregulating GRP75 expression. This disrupts the formation of the VDAC-GRP75-IP3R axis, which comprises critical tethering proteins responsible for endoplasmic reticulum to mitochondria coupling and Ca2+ trafficking. Knockdown of Grp75 inhibits the formation of MAM and prevents mitochondrial Ca2+ overload, improving mitochondrial quality and inhibiting PANoptosis in RPE cells, thereby interrupting the progression of experimental dAMD in Dapl1-deficient mice. These results unveil the role of MAMs regulated by DAPL1 in RPE cell PANoptosis and AMD progression, highlighting targeting MAM formation as a potential therapeutic strategy for treating dAMD.

Keywords: AMD; GRP75; PANoptosis; RPE; mitochondria-associated ER membrane

DOI: https://doi.org/10.1073/pnas.2511926123

Free Radic Biol Med. 2026 Feb 13. pii: S0891-5849(26)00131-0. [Epub ahead of print]247 435-447

Pigment epithelium-derived factor and osteopontin protect human retinal pigment epithelial cells from oxidative stress in 2D and 3D models.

Samira Karami, Pascale Charpentier, Solange Landreville, Stéphanie Proulx.

Retinal pigment epithelial (RPE) cells are particularly vulnerable to oxidative stress. Neighboring choroidal melanocytes (CMs) secrete trophic factors, such as pigment epithelium-derived factor (PEDF) and osteopontin (OPN), which may mitigate oxidative damage in RPE cells. Herein, we investigated the ability of PEDF and OPN to protect RPE cells from extended NaIO3-induced oxidative stress damage. Primary human RPE cells were seeded on plastic (2D culture) or on a 3D tissue-engineered choroidal stroma (TECS) containing (or not) CMs. PEDF or OPN was added before, during, and after 5 days of NaIO3 exposure. Analyses included assessment of PEDF and OPN expression, intracellular reactive oxygen species (ROS), lipid peroxidation, mitochondrial superoxide, cell death, antioxidant capacity (TAC) and p-Nrf2 nuclear translocation. Adding exogenous PEDF to the growth media stimulated de novo PEDF secretion by RPE cells, whereas OPN concentration detected in the growth media corresponded to the amount added. PEDF and OPN levels were consistently lower in the growth media of 3D TECS compared to the 2D cultures. Oxidative stress significantly increased intracellular ROS, lipid peroxidation, and RPE cell death in both 2D and 3D cultures, which were reduced by PEDF or OPN supplementation. Oxidative stress and PEDF or OPN supplementation did not alter the TAC of RPE cells. PEDF or OPN supplementation promoted p-Nrf2 nuclear translocation in RPE cells on plastic, even without oxidative stress, whereas this response was not observed in 3D TECS cultures. Adding CMs to the 3D TECS did not influence p-Nrf2 nuclear translocation in RPE cells. Overall, PEDF and OPN supplementation significantly protected human RPE cells against NaIO3-induced oxidative stress damage. In 3D TECS, CMs secreted insufficient levels of PEDF and OPN for RPE cells to manage oxidative stress-induced damage. These findings demonstrate that exogenous supplementation with PEDF and OPN proteins may be beneficial for oxidative-stress related eye diseases.

Keywords: Age-related macular degeneration (AMD); Cell death; Extended oxidative stress; Lipid peroxidation; Nrf2 nuclear translocation; Osteopontin (OPN); Pigment epithelium-derived factor (PEDF); Reactive oxygen species (ROS); Retinal pigment epithelium (RPE); Tissue-engineered choroidal stroma (TECS)

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.02.034

Aging Cell. 2026 Feb;25(2): e70416

Zhi-Yuan Li, Dashuang Yang, Yongxia Huang, Yintian Li, Tianyun Zhao, Ying Xu.

Age-related macular degeneration (AMD) stands as a leading cause of blindness in the elderly, yet the fundamental aging processes that underpin its pathogenesis remain incompletely defined. The dysfunction of retinal pigment epithelial (RPE) cells is a central event in AMD, a process that shares key hallmarks with broader cellular aging, particularly the progressive decline in mitochondrial function. In this study, we investigated how a common environmental stressor-blue light-triggers a key pathological transformation, epithelial-mesenchymal transition (EMT), in RPE cells by specifically disrupting mitochondrial dynamics, a core pillar of cellular aging. Using an in vitro model of human RPE cells, we demonstrated that blue light exposure induces a marked shift in mitochondrial dynamics towards excessive fission. This imbalance directly resulted in mitochondrial dysfunction, elevated oxidative stress, and served as the critical driver for the initiation of EMT. Importantly, pharmacological inhibition of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1) with Mdivi-1 effectively restored mitochondrial network homeostasis, rescued mitochondrial function, and fully reversed the EMT phenotype. These findings were corroborated in a mouse model of blue light-induced retinal damage, where Drp1 inhibition successfully preserved retinal light responses, mitigated structural degeneration, and slowed disease progression. Our study demonstrates that Drp1-mediated excessive mitochondrial fission drives EMT in RPE cells under blue light, linking this mechanism to AMD progression. Consequently, targeting mitochondrial dynamics to maintain cellular homeostasis emerges as a promising and broadly applicable geroscience-based strategy for mitigating age-related tissue dysfunction.

Keywords: Drp1; age‐related macular degeneration; epithelial‐mesenchymal transition; mitochondrial dynamics; oxidative stress; retinal pigment epithelial

DOI: https://doi.org/10.1111/acel.70416

Exp Eye Res. 2026 Feb 18. pii: S0014-4835(26)00088-6. [Epub ahead of print] 110932

SREBP1-Driven SCD1 Protects Retinal Pigment Epithelium from Oxidative Damage by Activating the NRF2/GPX4 Axis.

Xingyu Yang, Weichen Xu, Hang Xie, Xiaoyu Guo, Feiyan Zhu, Yiqiao Xing, Changzheng Chen.

This study reveals the pivotal role of the Sterol Regulatory Element-Binding Protein 1 (SREBP1)/Stearoyl-CoA Desaturase 1 (SCD1) lipid metabolic axis in protecting retinal pigment epithelium (RPE) against oxidative damage. We demonstrate SCD1 downregulation in age-related macular degeneration (AMD) patient tissues and sodium iodate (SI)-induced models, while its overexpression enhances cell viability and ameliorates oxidative injury. Mechanistically, we uncover a novel pathway where SCD1-derived oleic acid activates the nuclear factor erythroid 2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) signaling cascade, scavenging reactive oxygen species (ROS) and suppressing lipid peroxidation. Notably, oleic acid also mitigated oxidative stress via this pathway without directly promoting cell survival. These results not only elucidate SCD1's crucial protective mechanism in AMD pathogenesis but also establish the SREBP1/SCD1 axis as a promising therapeutic target for developing innovative interventions against retinal degeneration.

Keywords: Lipid peroxidation; Oleic acid (OA); Oxidative stress; Reactive Oxygen Species (ROS); Stearoyl-CoA Desaturase 1 (SCD1); Sterol Regulatory Element-Binding Protein 1(SREBP1); retinal pigment epithelium (RPE) cells

DOI: https://doi.org/10.1016/j.exer.2026.110932

Biochem Biophys Rep. 2026 Mar;45 102477

Functional polymorphisms in pigmentation-related genes MC1R and DCT display population-specific association with wet age-related macular degeneration.

Age-related macular degeneration (AMD) is among the leading causes of vision loss. Factors increasing the risk of AMD include aging, smoking, cardiovascular diseases and heritability. Although melanin pigment is known to protect retinal homeostasis, the link between pigmentation-related genes and AMD is unclear. We investigated associations between 26 variations in six pigmentation-related genes and wet AMD risk in a Finnish population, followed by replication in the United Kingdom (UK), Hungarian and Polish cohorts, totaling 775 patients and 959 controls. Associations of genetic components with smoking and body mass index (BMI) were tested in the Finnish and UK cohorts. The functionality of candidate variants in human retinal pigment epithelial (RPE) cells was evaluated using gene promoter analysis and gene silencing. Non-coding variants, rs1407995 in the dopachrome tautomerase (DCT) intron and rs3212351 in the melanocortin-1 receptor (MC1R) promoter, were associated with wet AMD in the Finnish cohort. The variant rs3212351 disrupts a binding site for transcription factor MITF and reduces MC1R expression in RPE cells. Unlike in the Finnish cohort, the data regarding the MC1R variant suggested a protective association in the Polish cohort. The incidence of AMD increased with age in all cohorts. Smoking increased AMD risk in the cohorts studied. Sex and BMI showed no associations. These findings suggest that variations in DCT and MC1R genes known to affect skin and eye pigmentation may also play a role in development of wet AMD. The observed population differences may be related to variable pigmentation traits.

Keywords: Dopachrome tautomerase; Melanocortin-1 receptor; Pigmentation; Polymorphism; Wet age-related macular degeneration

DOI: https://doi.org/10.1016/j.bbrep.2026.102477