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J. Biol. Chem., Vol. 283, Issue 36, 24770-24780, September 5, 2008

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The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells^*

Cristofol Vives-Bauza¹², Monika Anand¹, Arash K. Shirazi, Jordi Magrane, Junping Gao^¶, Heidi R. Vollmer-Snarr^¶3, Giovanni Manfredi, and Silvia C. Finnemann, Recipient of a William and Mary Greeve Scholarship by Research To Prevent Blindness, Inc., and of an Irma T. Hirschl Career Scientist Award^||4

From the Department of Neurology and Neuroscience, the Department of Ophthalmology, Dyson Vision Research Institute, and the ^||Departments of Physiology and Biophysics and of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065 and the ^¶Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602

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.

Received for publication, January 28, 2008 , and in revised form, June 26, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01-EY13295 (to S. C. F.) and K02-NS47306 (to G. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this study.

² Supported by a fellowship of the Ministerio de Educacion y Ciencia Fulbright program from the Spanish Ministry of Education and Science.

³ Supported by the donors of Macular Degeneration Research, a program of the American Health Assistance Foundation.

⁴ To whom correspondence should be addressed: Dyson Vision Research Institute, LC305, Box 233, Weill Cornell Medical College, 1300 York Ave., New York, NY 10065. Tel.: 212-746-2278; Fax: 212-746-8884; E-mail: sfinne{at}med.cornell.edu.

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