Age-related macular degeneration. The lipofusion 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 from age-related macular degeneration (AMD), the leading cause of severe visual impairment in humans living in developed countries. The pathogenesis of this complex disease is poorly understood, and no efficient therapy or prevention exists to date. A precondition for AMD appears to be the accumulation of the age pigment lipofuscin in lysosomes of retinal pigment epithelial (RPE) cells. In AMD, these cells seem to die by apoptosis with subsequent death of photoreceptor cells, and light may accelerate the disease process. Intracellular factors leading to cell death are not known. Here we show that the lipophilic cation N-retinyl-N-retinylidene ethanolamine (A2E), a lipofuscin component, induces apoptosis in RPE and other cells at concentrations found in human retina. Apoptosis is accompanied by the appearance of the proapoptotic proteins cytochrome c and apoptosis-inducing factor in the cytoplasm and the nucleus. Biochemical examinations show that A2E specifically targets cytochrome oxidase (COX). With both isolated mitochondria and purified COX, A2E inhibits oxygen 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 dehydrogenase activity is not altered by A2E. We suggest that A2E can act as a proapoptotic molecule via a mitochondria-related mechanism, possibly through site-specific targeting of this cation to COX. Loss of RPE cell viability through inhibition of mitochondrial function might constitute a pivotal step toward the progressive degeneration of the central retina.
Suter
M
M
Institute of Biochemistry, Swiss Federal Institute of Technology, Universitätstr. 16, CH-8092 Zurich, Switzerland.
Remé
C
C
Grimm
C
C
Wenzel
A
A
Jäättela
M
M
Esser
P
P
Kociok
N
N
Leist
M
M
Richter
C
C
D000375:Aging; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D002308:Cardiolipins / Q000494:pharmacology; D002412:Cations; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003574:Cytochrome c Group / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005420:Flavoproteins / Q000378:metabolism; D007150:Immunohistochemistry; D007536:Isomerism; D008027:Light; D008062:Lipofuscin / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D009113:Muramidase / Q000378:metabolism; D010101:Oxygen Consumption; D010786:Photoreceptor Cells / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012168:Retinal Pigments / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism*; D013552:Swine
C112040:A2-E (N-retinylidene-N-retinylethanolamine); C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D002308:Cardiolipins; D002412:Cations; D003574:Cytochrome c Group; D005420:Flavoproteins; D008062:Lipofuscin; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D012168:Retinal Pigments; D012176:Retinoids; D003576:Electron Transport Complex IV; D009113:Muramidase