Age-related macular degeneration - The lipofuscin component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells

10-20% of individuals over the age of 65 suffer hom age-related macular deg eneration (ARID), the leading cause of severe visual impairment in humans l iving in developed countries, The pathogenesis of this complex disease is p oorly understood, and no efficient therapy or prevention exists to date. A precondition for ARID appears to be the accumulation of the age pigment lip ofuscin in lysosomes of retinal pigment epithelial (RPE) cells. In AMD, the se cells seem to die by apoptosis with subsequent death of photoreceptor ce lls, and light may accelerate the disease process. Intracellular factors le ading to cell death are not known. Here we show that the lipophilic cation N-retinyl-N-retinylidene ethanolamine (A2E), a lipofuscin component, induce s apoptosis in RPE and other cells at concentrations found in human retina. Apoptosis is accompanied by the appearance of the proapoptotic proteins cy tochrome c and apoptosis-inducing factor in the cytoplasm and the nucleus. Biochemical examinations show that A2E specifically targets cytochrome oxid ase (COX). With both isolated mitochondria and purified COX, A2E inhibits o xygen consumption synergistically with light. Inhibition is reversed by the addition of cytochrome c or cardiolipin, a negatively charged phospholipid that facilitates the binding of cytochrome c to membranes, Succinate dehyd rogenase activity is not altered by A2E, We suggest that A2E can act as a p roapoptotic molecule via a mitochondria-related mechanism, possibly through site-specific targeting of this cation to COX Loss of RPE cell viability t hrough inhibition of mitochondrial function might constitute a pivotal step toward the progressive degeneration of the central retina.