The 11-cis Retinal Origins of Lipofuscin in the Retina

Lipofuscin is a fluorescent mixture of partially digested proteins and lipids that accumulates with age in the lysosomal compartment of the retinal pigment epithelium (RPE) of the eye. Because it has been found to have significant cytotoxic potential, lipofuscin is thought to play a role in retinal degeneration diseases including age-related macular degeneration and Stargardt disease, a form of juvenile macular degeneration. The only known components of lipofuscin are bis-retinoids, the condensation products of two molecules of retinal. The bulk of lipofuscin is thought to originate in the rod photoreceptor outer segments as a by-product of reactions involving the retinal chromophore of rhodopsin. 11-cis retinal flows from the RPE into the rod outer segments, where it combines with opsin to form rhodopsin; all-trans retinal is released into the rod outer segments by photoactivated rhodopsin following its excitation by light. Both 11-cis and all-trans retinal can generate lipofuscin-like fluorophores and bis-retinoids when added to rod outer segment membranes. The levels of lipofuscin precursor fluorophores present in the outer segments of dark-adapted rods are similar in cyclic-light-and dark-reared mice, as are the levels of accumulated lipofuscin in the RPE. Because the retinol dehydrogenase enzyme present in rod outer segments can reduce all-trans but not 11-cis retinal, lipofuscin precursors are more likely to form from 11-cis than all-trans retinal, even under cyclic light conditions. Thus, 11-cis retinal may be the primary source of lipofuscin in the retina.