April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Altered Outer Segment Phagocytosis Causes RPE Mitochondrial Dysfunction: Molecular Mechanisms
Author Affiliations & Notes
  • S. C. Finnemann
    Biological Sciences, Fordham University, Bronx, New York
  • C.-C. Yu
    Biological Sciences, Fordham University, Bronx, New York
  • Y. Dun
    Biological Sciences, Fordham University, Bronx, New York
  • Footnotes
    Commercial Relationships  S.C. Finnemann, None; C.-C. Yu, None; Y. Dun, None.
  • Footnotes
    Support  NIH Grant EY13295, The California Table Grape Commission
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 499. doi:
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      S. C. Finnemann, C.-C. Yu, Y. Dun; Altered Outer Segment Phagocytosis Causes RPE Mitochondrial Dysfunction: Molecular Mechanisms. Invest. Ophthalmol. Vis. Sci. 2010;51(13):499.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : In mice lacking the integrin recognition receptor αvβ5, oxidative processes secondary to loss of the diurnal rhythm of photoreceptor outer segment phagocytosis cause age-related loss of photoreceptor function (but not viability) and RPE lipofuscin accumulation. We seek to explore this experimental model to elucidate how changes in phagocytic capacity or kinetics of the RPE (1) specifically cause oxidative stress, (2) how such chronic, sublethal oxidative stress alters RPE functionality causing age-related retinal disease, and (3) how we can prevent secondary oxidative damage to retina/RPE preserving photoreceptor function in vivo.

Methods: : We explored primary cultures of RPE derived from mice with complete or defective phagocytic machineries that were exposed to different sources of oxidative stress in assays quantifying experimental outer segment uptake, reactive oxygen species, or mitochondrial activity. We determined levels, phosphorylation, oxidative modification and subcellular localization of phagocytic signaling proteins in these cells using immunoblotting and laser scanning confocal microscopy. Furthermore, we tested in vivo oxidative burden, phagocytic signaling, and mitochondrial functionality in RPE/retina of wild-type and β5 null mice fed or not diet supplemented with grapes rich in antioxidants.

Results: : Our experiments demonstrate that RPE cells lacking αvβ5 integrin are more sensitive to accumulation of the lipofuscin component A2E or to sublethal levels of hydrogen peroxide than RPE cells that possess a complete phagocytic machinery. Phagocytosis of photoreceptor outer segments further enhances this discrepancy by increasing intracellular reactive oxygen species. Our data also suggest that this is due to altered phagocytic signaling pathways and that a major target of reactive oxygen species produced by β5 null RPE in vivo and in vitro is the mitochondrial respiratory chain.

Conclusions: : Cumulative oxidative damage of the RPE leads to formation of pro-oxidant lipofuscin and contributes to RPE and retinal atrophy in dry AMD. Our work pinpoints molecular changes due to delayed phagocytosis of outer segments shed daily by photoreceptor cells as possible causative factor in RPE mitochondrial dysfunction that can be directly responsible for such outcome.

Keywords: retinal pigment epithelium • retinal degenerations: cell biology • mitochondria 

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