ArticleProceedings of the National Academy of Sciences of the United States of America2016
Protective responses to sublytic complement in the retinal pigment epithelium.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 61 citations in OpenAlex.
- Lipid-driven membrane remodeling engages a lysosome-dependent adaptive repair program during retinal aging.Molecular neurodegeneration · 2026Article
- Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Acid sphingomyelinase inhibition restores RPE homeostasis and photoreceptor function in preclinical Stargardt macular degeneration models.bioRxiv : the preprint server for biology · 2026Article
- Review
- Action of the Terminal Complement Pathway on Cell Membranes.The Journal of membrane biology · 2025Review
- VEGF in Diabetic Retinopathy and Age-Related Macular Degeneration.International journal of molecular sciences · 2025Review
- Gene therapy for age-related macular degeneration: a promising frontier in vision preservation.Cell communication and signaling : CCS · 2025Review
- How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.Experimental eye research · 2025Review
- Roles of MASP-1 and MASP-3 in the development of retinal degeneration in a murine model of dry age-related macular degeneration.Frontiers in immunology · 2025Article
- Aberrant Lipid Metabolism and Complement Activation in Age-Related Macular Degeneration.Investigative ophthalmology & visual science · 2024Review
- Aging of the eye: Lessons from cataracts and age-related macular degeneration.Ageing research reviews · 2024Review
- Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD.Gene therapy · 2024Article
- Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System.Aging and disease · 2024Review
- Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease.Frontiers in ophthalmology · 2024Article
- The Relationship between Complements and Age-Related Macular Degeneration and Its Pathogenesis.Journal of ophthalmology · 2024Review
- Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina.Current biology : CB · 2023Article
- Comparative mechanistic study of RPE cell death induced by different oxidative stresses.Redox biology · 2023Article
- Apolipoprotein ε in Brain and Retinal Neurodegenerative Diseases.Aging and disease · 2023Review
- Bruch's Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration.Journal of clinical medicine · 2023Review
- Increased plasma level of terminal complement complex in AMD patients: potential functional consequences for RPE cells.Frontiers in immunology · 2023Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4(-/-) Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4(-/-) mice, indicating that they could be effective therapeutic approaches for macular degenerations.
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