The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells.

Show simple item record

dc.contributor.author Vives-Bauza, Cristòfol
dc.contributor.author Anand, Mónica
dc.contributor.author Shiraz, Arash K.
dc.contributor.author Magrane, Jordi
dc.contributor.author Gao, Junping
dc.contributor.author Vollmer-Snarr Heidi R.
dc.contributor.author Manfredi, Giovanni
dc.contributor.author Finnemann, Silvia C.
dc.date.accessioned 2018-10-04T10:48:55Z
dc.identifier.uri http://hdl.handle.net/11201/147921
dc.description.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.
dc.format application/pdf
dc.relation.isformatof Versió postprint del document publicat a: https://doi.org/10.1074/jbc.M800706200
dc.relation.ispartof Journal of Biological Chemistry, 2008, vol. 283, num. 36, p. 24770-24780
dc.subject.classification 54 - Química
dc.subject.other 54 - Chemistry. Crystallography. Mineralogy
dc.title The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells.
dc.type info:eu-repo/semantics/article
dc.type info:eu-repo/semantics/acceptedVersion
dc.date.updated 2018-10-04T10:48:55Z
dc.date.embargoEndDate info:eu-repo/date/embargoEnd/2075-01-01
dc.embargo 2075-01-01
dc.rights.accessRights info:eu-repo/semantics/embargoedAccess
dc.identifier.doi https://doi.org/10.1074/jbc.M800706200


Files in this item

This item appears in the following Collection(s)

Show simple item record