Activated mTOR Signaling in the RPE Drives EMT, Autophagy, and Metabolic Disruption, Resulting in AMD‐Like Pathology in Mice

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Although the role mTORC1 in retinal pigmented epithelium (RPE) homeostasis age-related macular degeneration (AMD) pathogenesis is established, function mTORC2 remains unclear. We investigated both RPE health disease. Therefore, this study, we have attempted to demonstrate that specific overexpression mammalian lethal with Sec13 protein 8 (mLST8) mouse activates mTORC2, inducing epithelial-mesenchymal transition (EMT)-like changes subretinal/RPE deposits resembling early AMD-like pathogenesis. Aging these mice leads degeneration, causing damage, impaired debris clearance, metabolic mitochondrial dysfunction. Inhibition mTOR TORIN1 vitro or βA3/A1-crystallin vivo normalized mTORC1/2 activity restored function, revealing a novel regulating impacting

Язык: Английский

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Recent advances in fluorescent probes for ATP imaging

Talanta, Год журнала: 2024, Номер 279, С. 126622 - 126622

Опубликована: Июль 28, 2024

Язык: Английский

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Gastrodin ameliorates oxidative stress-induced RPE damage by facilitating autophagy and phagocytosis through PPARα-TFEB/CD36 signal pathway

Free Radical Biology and Medicine, Год журнала: 2024, Номер 224, С. 103 - 116

Опубликована: Авг. 22, 2024

Язык: Английский

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Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress–Induced RPE Degeneration

Investigative Ophthalmology & Visual Science, Год журнала: 2025, Номер 66(2), С. 2 - 2

Опубликована: Фев. 3, 2025

Autophagy and lysosomal degradation are vital processes that protect cells from oxidative stress. This study investigated the role of lysosome-associated membrane protein 2 (Lamp2), a essential for autophagosome maturation lysosome biogenesis, in maintaining retinal health under To induce stress, young Lamp2 knockout (KO) wild-type mice received an intravenous injection low dose (10 mg/kg) sodium iodate (NaIO3). We examined histopathology morphological changes RPE. The involvement resident microglia or infiltrating macrophages was assessed using immunostaining, flow cytometry, real-time PCR chemokines cytokines. After administering low-dose NaIO3, KO showed significant RPE degeneration, whereas had minimal damage. Histological analysis electron microscopy revealed thinning outer nuclear layer loss epithelial polarity mice. Additionally, there increase ionized calcium-binding adaptor molecule 1-positive retina. Early proliferation CD45lowMHC-IIlow followed by infiltration CD45highLy6Chigh monocytes engraftment CD11b+CD45high monocyte-derived macrophages. Transcript levels monocyte chemoattractant 1, macrophage inflammatory 1β, Il- Il-6 also increased retinas Furthermore, pretreatment with macrophage-depleting agent clodronate prevented NaIO3-induced degeneration deficiency, when combined leads to vivo. Lysosomal dysfunction promotes triggers neurotoxic inflammation.

Язык: Английский

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Neurological Emergency Treatment Strategy: A Neuron-Targeted Regulation System for Reactive Oxygen Species Metabolism through Ferroptosis Modulation

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Spinal cord injury (SCI) represents a significant clinical challenge. Following SCI, the implementation of protective measures for neurons is critically important. Current applications hormone pulse therapy exhibit variable efficacy and considerable side effects, highlighting an urgent need therapeutic strategies. This study investigates pathological conditions ischemia hypoxia in SCI region, complemented by early transcriptome sequencing postinjury. Our findings suggest that targeting ferroptosis pivotal neuroprotection following SCI. Aiming at cascade effect mitochondrial damage leading to reactive oxygen species (ROS) production, along with extensive ROS-mediated lysosomal during signaling, we developed liposome-based system regulating iron metabolism─DTLS@CAT. innovative liposome designed specifically target neuronal mitochondria, effectively eliminate mitoROS, modulate complex interactions among metabolism, lysosomes, ROS facilitate recovery from

Язык: Английский

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Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy

The American Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

SummaryInherited retinal diseases (IRDs) are a genetically heterogeneous group of Mendelian disorders that often lead to progressive vision loss and involve approximately 300 distinct genes. Although variants in these loci account for the majority molecular diagnoses, other genes associated with IRD await identification. In this study, we uncover bi-allelic assortments 23 different (22 loss-of-function) AP5Z1, AP5M1, AP5B1 as independent causes recessive members 19 families from nine countries. Affected individuals, regardless their genotypes, exhibit specific form macular degeneration, sometimes presenting association extraocular features. All three encode subunits vesicular fifth adaptor protein (AP-5) complex, component intracellular trafficking system involved maintaining cellular homeostasis ensuring proper functioning lysosomal pathways. The pigment epithelium (RPE), monolayer located posteriorly neural retina, is characterized by intense phagocytic activity. Immunostaining RPE cells revealed punctate pattern staining co-localization markers late endosomes Golgi, suggesting role AP-5 normal physiology tissue. Overall, identification independently acting proteins within same macromolecular complex reveals having an important function preservation maintenance functions.Graphical abstract

Язык: Английский

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Metabolic Phenotyping of Healthy and Diseased Human RPE Cells

Investigative Ophthalmology & Visual Science, Год журнала: 2024, Номер 65(11), С. 5 - 5

Опубликована: Сен. 4, 2024

Metabolic defects in the retinal pigment epithelium (RPE) underlie many degenerative diseases. This study aims to identify nutrient requirements of healthy and diseased human RPE cells.

Язык: Английский

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Polarity-Targeted Carbon Dots for Mitochondria and Lysosomes Imaging

Analytical Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 14, 2024

Normally, electrostatic-dependent mitochondria localization can cause a decrease/loss of mitochondrial membrane potential (MMP), leading to the corresponding abnormal behaviors. So, achieving subcellular organelle and imaging with as little interference on their physiological activity is significance for understanding cell activity. Herein, we discover demonstrate that "polarity" independently act novel kind target labeling at level. On this basis, lysosomes are precisely fluorescently imaged by two kinds polarity-targeted carbon dots (C-dots), respectively. The C-dots, named C-dots-1 C-dots-2, have almost identical size morphology well surface chemistry. subtle difference polarity property: both them amphiphilic, 1.54 0.95 log P values. Different from commonly used cationic-based probes, C-dots possess slightly negatively charged surfaces (ζ-potential values ∼ -2.5 -7.5 mV) conditions. Interestingly, C-dots-2 capacity highly selectively lysosomes, whether cancer cells or normal cells. Because targeting processes do not rely electrostatic attraction effects, MMP changed during processes. behaviors caused diminishing, example, autophagy phenomenon, be effectively avoided.

Язык: Английский

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Strategic delivery of rapamycin and ranibizumab with intravitreal hydrogel depot disrupts multipathway-driven angiogenesis loop for boosted wAMD therapy

Journal of Controlled Release, Год журнала: 2024, Номер 377, С. 239 - 255

Опубликована: Ноя. 21, 2024

Язык: Английский

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Metabolic phenotyping of healthy and diseased human RPE cells

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 2, 2024

Abstract Purpose Metabolic defects in the retinal pigment epithelium (RPE) underlie many degenerative diseases. This study aims to identify nutrient requirements of healthy and diseased human RPE cells. Methods We profiled utilization various cells, including differentiated dedifferentiated fetal (fRPE), induced pluripotent stem cell derived-RPE (iPSC RPE), Sorsby fundus dystrophy (SFD) patient-derived iPSC RPE, CRISPR-corrected isogenic SFD (cSFD) ARPE-19 lines using Biolog Phenotype MicroArray Assays. Results Differentiated fRPE cells can utilize 51 48 nutrients respectively, sugars, intermediates from glycolysis tricarboxylic acid (TCA) cycle, fatty acids, ketone bodies, amino dipeptides. However, when lose their epithelial phenotype through dedifferentiation, becomes restricted 17 nutrients, primarily sugar glutamine-related acids. 37 nutrients; however, compared cSFD they are unable lactate, some TCA cycle intermediates, short-chain Nonetheless, show increased branch-chain acids (BCAAs) BCAA-containing Dedifferentiated grown traditional culture media cannot lactate bodies. In contrast, nicotinamide supplementation promotes differentiation towards an phenotype, restoring ability use these nutrients. Conclusions Epithelial confers metabolic flexibility for utilizing have reduced flexibility, relying on oxidation BCAAs. Our findings highlight potentially important roles availability

Язык: Английский

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