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The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells.
The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2008 Sep 05; Vol. 283 (36), pp. 24770-80. Date of Electronic Publication: 2008 Jul 10. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Adenosine Triphosphate genetics
Adenosine Triphosphate metabolism
Aging genetics
Aging pathology
Animals
Antioxidants metabolism
Antioxidants pharmacology
Cell Death drug effects
Cell Death genetics
Cell Line
DNA, Mitochondrial genetics
DNA, Mitochondrial metabolism
Epithelial Cells metabolism
Epithelial Cells pathology
Glucose metabolism
Humans
Lipofuscin pharmacology
Lysosomes genetics
Lysosomes metabolism
Lysosomes pathology
Macular Degeneration genetics
Macular Degeneration metabolism
Macular Degeneration pathology
Membrane Potential, Mitochondrial drug effects
Membrane Potential, Mitochondrial genetics
Mitochondria genetics
Mitochondria pathology
Mitosis drug effects
Mitosis genetics
Oxidative Phosphorylation drug effects
Pigment Epithelium of Eye pathology
Point Mutation
Pyridinium Compounds pharmacology
Pyruvic Acid metabolism
Rats
Rats, Long-Evans
Retinoids pharmacology
Aging metabolism
Lipofuscin metabolism
Mitochondria metabolism
Phagocytosis drug effects
Phagocytosis genetics
Pigment Epithelium of Eye metabolism
Pyridinium Compounds metabolism
Retinoids metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 283
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18621729
- Full Text :
- https://doi.org/10.1074/jbc.M800706200