The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells
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Accumulation of indigestible lipofuscin and decreased mitochondrial energy production are characteristic age-related changes of post-mitotic retinal pigment epithelial (RPE) cells in the human eye. To test whether these two forms of age-related impairment have interdependent effects, we quantified the ATP-dependent phagocytic function of RPE cells loaded or not with the lipofuscin component A2E and inhibiting or not mitochondrial ATP synthesis either pharmacologically or genetically. We found that physiological levels of lysosomal A2E reduced mitochondrial membrane potential and inhibited oxidative phosphorylation (OXPHOS) of RPE cells. Furthermore, in media with physiological concentrations of glucose or pyruvate, A2E significantly inhibited phagocytosis. Antioxidants reversed these effects of A2E, suggesting that A2E damage is mediated by oxidative processes. Because mitochondrial mutations accumulate with aging, we generated novel genetic cellular models of RPE carrying mitochondrial DNA point mutations causing either moderate or severe mitochondrial dysfunction. Exploring these mutant RPE cells we found that, by itself, only the severe but not the moderate OXPHOS defect reduces phagocytosis. However, sub-toxic levels of lysosomal A2E are sufficient to reduce phagocytic activity of RPE with moderate OXPHOS defect and cause cell death of RPE with severe OXPHOS defect. Taken together, RPE cells rely on OXPHOS for phagocytosis when the carbon energy source is limited. Our results demonstrate that A2E accumulation exacerbates the effects of moderate mitochondrial dysfunction. They suggest that synergy of sub-toxic lysosomal and mitochondrial changes in RPE cells with age may cause RPE dysfunction that is known to contribute to human retinal diseases like age-related macular degeneration.
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A2E and mitochondrial dysfunction are reported to impair RPE phagocytosis and activate the complement system.
“A2E (a by-product of phototransduction, present in lipofuscin) and mitochondrial dysfunction are reported to impair RPE phagocytosis and activate the complement system (156, 178).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [156]
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- Authors
- Vives-Bauza, C., Anand, M., Shirazi, A. K., Magrane, J., Gao, J., Vollmer-Snarr, H. R., Manfredi, G., & Finnemann, S. C.
- Affiliations
- Cornell University (US)
- Brigham Young University (US)
- Corresponding author
- Finnemann, Silvia C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 283
- Issue
- 36
- Pages
- 24770-24780
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2529005
- OpenAlex
- W2021234912
- Cited by
- 155
- References
- 54
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 8 · 2020: 13 · 2019: 6 · 2018: 12 · 2017: 8 · 2016: 4 · 2015: 9 · 2014: 17 · 2013: 9 · 2012: 13
- FWCI
- 8.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fulbright Program
- American Health Assistance Foundation
- Research to Prevent Blindness
- National Institutes of Health
- National Eye Institute (R01 EY13295, R01EY013295)
- National Institute of Neurological Disorders and Stroke (K02 NS 47306, K02NS047306)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- retinal pigment epithelium, phagocytosis, mitochondrial dysfunction, oxidative phosphorylation, mitochondrial membrane potential, aging, mitochondrial DNA mutations, lysosomal accumulation, oxidative stress, age-related macular degeneration, RPE cell death
- MeSH terms
- Adenosine Triphosphate, Aging, Animals, Antioxidants, Cell Line, DNA, Mitochondrial, Epithelial Cells, Glucose, Humans, Lipofuscin, Lysosomes, Macular Degeneration, Mitochondria, Mitosis, Oxidative Phosphorylation, Phagocytosis, Pigment Epithelium of Eye, Pyridinium Compounds, Retinoids, Cell Death, Point Mutation, Pyruvic Acid, Rats, Long-Evans, Rats, Membrane Potential, Mitochondrial
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