Document Detail


The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells.
MedLine Citation:
PMID:  18621729     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Cristofol Vives-Bauza; Monika Anand; Ashton K Shiraz; Arash K Shirazi; Jordi Magrane; Junping Gao; Heidi R Vollmer-Snarr; Giovanni Manfredi; Silvia C Finnemann
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-07-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-01     Completed Date:  2008-10-20     Revised Date:  2014-09-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24770-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / genetics,  metabolism
Aging / genetics,  metabolism*,  pathology
Animals
Antioxidants / metabolism,  pharmacology
Cell Death / drug effects,  genetics
Cell Line
DNA, Mitochondrial / genetics,  metabolism
Epithelial Cells / metabolism,  pathology
Glucose / metabolism
Humans
Lipofuscin / metabolism*,  pharmacology
Lysosomes / genetics,  metabolism,  pathology
Macular Degeneration / genetics,  metabolism,  pathology
Membrane Potential, Mitochondrial / drug effects,  genetics
Mitochondria / genetics,  metabolism*,  pathology
Mitosis / drug effects,  genetics
Oxidative Phosphorylation / drug effects
Phagocytosis* / drug effects,  genetics
Pigment Epithelium of Eye / metabolism*,  pathology
Point Mutation
Pyridinium Compounds / metabolism*,  pharmacology
Pyruvic Acid / metabolism
Rats
Rats, Long-Evans
Retinoids / metabolism*,  pharmacology
Grant Support
ID/Acronym/Agency:
K02 NS047306/NS/NINDS NIH HHS; K02 NS047306-04/NS/NINDS NIH HHS; K02 NS047306-05/NS/NINDS NIH HHS; K02-NS47306/NS/NINDS NIH HHS; R01 EY013295/EY/NEI NIH HHS; R01-EY13295/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/A2E compound; 0/Antioxidants; 0/DNA, Mitochondrial; 0/Lipofuscin; 0/Pyridinium Compounds; 0/Retinoids; 8558G7RUTR/Pyruvic Acid; 8L70Q75FXE/Adenosine Triphosphate; IY9XDZ35W2/Glucose
Comments/Corrections
Erratum In:
J Biol Chem. 2013 Nov 8;288(45):32639
Note: Shirazi, Arash K [corrected to Shiraz, Ashton K]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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