bims-mideyd 2026-04-19 papers

Invest Ophthalmol Vis Sci. 2026 Apr 01. 67(4): 30

Modulation of Iron-Induced Glucose Metabolic Reprogramming Alleviates Retinal Pigment Epithelial Cell Senescence.

Purpose: This study aimed to investigate whether iron overload induces retinal pigment epithelial (RPE) cell senescence through glucose metabolic reprogramming and to evaluate the therapeutic potential of targeting this metabolic pathway.
Methods: We utilized human-induced pluripotent stem cell-derived RPE cells and induced RPE cells, along with mouse models with intravitreal or intraperitoneal injection of ferric ammonium citrate (FAC), to evaluate the effect of iron overload on RPE senescence. Proteomics, targeted metabolomics, reactive oxygen species (ROS) assay kits, JC-1 assay kit, reverse-transcription polymerase chain reaction, SA-β-gal staining, and western blot were used to assess mitochondrial function, ROS, and senescence markers. 2-Deoxy-d-glucose (2-DG), pyruvate kinase M2 inhibitor-1 (PKM2-IN-1), and sodium oxamate (SO) were used to modulate glucose metabolism flux. Flash electroretinography recording was used to assess visual function.
Results: Iron overload triggered significant glucose metabolic reprogramming in RPE cells, characterized by a time-dependent metabolic shift. Early exposure to FAC induced a transient surge in glucose metabolic flux, which elevated mitochondrial ROS production and disrupted mitochondrial homeostasis, ultimately leading to cellular senescence. Importantly, early inhibition of this metabolic surge with 2-DG or PKM2-IN-1 effectively attenuated senescence by reducing ROS levels and preserving mitochondrial function. Conversely, enhancing pyruvate flux with SO exacerbated senescence. The protective effect of 2-DG against iron-induced RPE senescence was further confirmed in a mouse model, where it preserved visual function and reduced senescence markers.
Conclusions: Glucose metabolic reprogramming mediates iron-induced RPE senescence, with transient glucose flux surge driving pathology via ROS-related mitochondrial damage. Targeting glucose metabolism may preserve mitochondria homeostasis and prevent RPE degeneration in age-related macular degeneration.

DOI: https://doi.org/10.1167/iovs.67.4.30

Mem Inst Oswaldo Cruz. 2026 ;pii: S0074-02762026000105025. [Epub ahead of print]121 e250141

Retinal pigment epithelium drives macrophage migration during Toxoplasma gondii infection in vitro

Alex Martins Nasaré, Roberto Carlos Tedesco, Paula Andrea Faria Waziry, Lorena de Paula Pantaleon, Esther Lopes Ricci, Luís Antônio Baffile Leoni, André Rinaldi Fukushima, Andres Jimenez Galisteo Junior.

BACKGROUND: Ocular toxoplasmosis is a leading cause of infectious posterior uveitis worldwide. The retinal pigment epithelium (RPE), a key barrier and immunomodulatory layer in the eye, is directly targeted by Toxoplasma gondii during infection. However, its role in orchestrating the local immune response remains unclear.
OBJECTIVES: To investigate whether RPE cells actively drive macrophage migration during T. gondii infection in vitro, and to identify associated cytokine profiles.
METHODS: Adult retinal pigment epithelial cells (ARPE)-19 and primary RPE cells were exposed to tachyzoites, soluble antigens or conditioned supernatants. Macrophage migration was assessed using Transwell® and under-agar assays. Cytokines were quantified by cytometric bead array.
FINDINGS: Both ARPE-19 and primary RPE exhibited chemotaxis toward parasite antigens (0.12 - 0.5 μg), and enhanced interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) secretion. Co-culture with RAW 264.7 macrophages further amplified cytokine production. Primary RPE from infected animals occluded 90% of Transwell® pores within 24h. IL-6 and IL-10 levels strongly correlated with migratory activity (r = 0.82 and 0.77, respectively).
MAIN CONCLUSIONS: RPE cells are not passive targets but active participants in the ocular immune response to T. gondii. By secreting IL-6 and IL-10, they establish a chemotactic environment that recruits macrophages. These insights identify the RPE-cytokine-macrophage axis as a potential therapeutic target in ocular toxoplasmosis.

DOI: https://doi.org/10.1590/0074-02760250141

Invest Ophthalmol Vis Sci. 2026 Apr 01. 67(4): 28

Oral Deuterated Docosahexaenoic Acid Protects Against Onset and Progression of RPE Degeneration in a Mouse Model of Chronic Oxidative Stress.

Sierra Foshe, Brandon D Anderson, Ying Song, Sophia Shi, Sarah Lee, Brent A Bell, Hui Gyu Park, J Thomas Brenna, Mikhail Shchepinov, Joshua L Dunaief.

Purpose: Oxidative stress is associated with many retinal diseases, including age-related macular degeneration (AMD). The purpose of this study is to investigate the efficacy of oral deuterated docosahexaenoic acid (D-DHA), an oxidation-resistant lipid, in a mouse model with features of dry AMD. We also evaluated whether long-term D-DHA dosing affects normal retinal structure or function.
Methods: Liver-specific hepcidin (Hepc) and ceruloplasmin/hepcidin (Cp/Hepc) knock-out (KO) mice were fed experimental diet containing 0.25% D-DHA or control containing normal H-DHA during various stages of disease progression. Retinal pigment epithelium (RPE) damage was assessed with in vivo scanning laser ophthalmoscopy (SLO) imaging and histology. For the safety study, wild-type mice were fed the diets beginning in utero or at 3 months of age, continuing for 12 months. These mice were analyzed to assess retinal structure (SLO, optical coherence tomography [OCT], and transmission electron microscopy [TEM]), function (ERG), and gene expression (qPCR).
Results: KO mice fed control diet developed expanding autofluorescent patches of hypertrophic RPE cells. This damage was markedly prevented or halted by diet with D-DHA, depending on age at diet onset. Wild-type mice administered diet with D-DHA from age 3 to 15 months had no retinal abnormalities. Mice administered D-DHA beginning in utero had normal retinal development and structure but minor deficits in ERG amplitudes and Rpe65 expression by age 12 months.
Conclusions: Oral D-DHA was strongly protective against RPE ferroptosis, with minimal side effects. This study suggests that DHA oxidation is a key mechanism of retinal iron toxicity and supports the potential clinical application of D-DHA for diseases involving retinal oxidative stress.

DOI: https://doi.org/10.1167/iovs.67.4.28

Cell Death Dis. 2026 Apr 13.

Human retinal organoid model of disease-relevant photoreceptor cell death amenable to drug screening.

Shama Parween, Anthony J Saviola, Anna C Howell, Stefanie Varghese, David Ceja Galindo, M Natalia Vergara.

Dry age-related macular degeneration (AMD) is characterized by the progressive loss of retinal pigment epithelium cells in the macula, leading to photoreceptor degeneration and loss of central vision. Current treatments only modestly delay disease progression, but once photoreceptors are damaged, vision loss becomes irreversible. Therefore, there is an urgent need to develop therapies that prevent photoreceptor cell death and that may complement current and emerging treatment strategies. A critical step toward this goal is establishing pathophysiologically relevant human disease models for therapeutic testing. In this study, we developed a human induced pluripotent stem cell-derived retinal organoid (RO) model that recapitulates key aspects of AMD-associated photoreceptor degeneration. To mimic environmental stressors relevant to AMD, we treated mature ROs with cigarette smoke extract (CSE), a known oxidative agent and major modifiable risk factor for the disease. CSE exposure induced oxidative stress, mitochondrial membrane depolarization, and cell death primarily in the outer nuclear layer. Photoreceptor degeneration in this model involves the activation of the intrinsic apoptotic pathway and ferroptosis, which is accompanied by lipid peroxidation and dysregulation of the glutathione system. Proteomic profiling confirmed alterations in metabolic, redox, and cell death pathways consistent with AMD pathophysiology, and offered further insight into the mechanistic interplay among these pathways. Furthermore, we integrated this model with robust, quantitative outcome measures in live ROs, offering a powerful platform for preclinical therapeutic screening in dry AMD.

DOI: https://doi.org/10.1038/s41419-026-08724-y

Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2504764123

Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease.

Simona Brillante, Mariagrazia Volpe, Anna Diana, Santiago Negueruela, Marta Molinari, Rosa Saurino, Eva Cipollaro, Elena Polishchuk, Erika Tenderini, Carla Damiano, Patrizia Tornabene, Roman Polishchuk, Giancarlo Parenti, Antonietta Tarallo, Sandro Banfi, Ivana Trapani, Sabrina Carrella, Alessia Indrieri.

Stargardt disease type 1 (STGD1) is the most common hereditary macular degeneration. It is caused by mutations in ABCA4, which result in the progressive degeneration of the retinal pigment epithelium (RPE), ultimately leading to photoreceptor loss. Despite extensive efforts, STGD1 currently lacks effective treatments. Here, we first identified mitochondrial defects in the photoreceptors of Abca4-/- mice and STGD1 patient-derived retinal organoids. Specifically, we found reduced mitochondrial content, defective cristae morphology, and downregulation of OPA1, a critical regulator of mitochondrial integrity, demonstrating that photoreceptor defects in STGD1 also have a cell-autonomous origin, besides the RPE dysfunction. Importantly, we also demonstrated that correcting this pathological phenotype through the modulation of microRNAs 181a and b (miR-181a/b), key regulators of mitochondrial function, ameliorates the STGD1 phenotype. Indeed, genetic inactivation and adeno-associated viral vector-mediated silencing of miR-181a/b in STGD1 models restored OPA1 levels, improved mitochondrial phenotype, and reduced lipofuscin accumulation in the RPE. Our study demonstrates that mitochondrial dysfunction in photoreceptors is an important contributor to STGD1 pathology, opening promising therapeutic avenues for this disorder.

Keywords: Stargardt disease; miR-181a/b; microRNA; mitochondria; photoreceptors

DOI: https://doi.org/10.1073/pnas.2504764123