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J. Biol. Chem., Vol. 275, Issue 50, 39625-39630, December 15, 2000
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From the 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.
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*
,
,,
Institute of Biochemistry, Swiss Federal
Institute of Technology, Universitätstr. 16, CH-8092 Zurich,
Switzerland, § Laboratory for Retinal Cell Biology,
Department of Ophthalmology, University Hospital Zurich,
Frauenklinikstr. 24, CH-8091 Zurich, Switzerland, ¶ Danish Cancer
Society, Apoptosis Laboratory, Strandboulevarden 49, DK-2100
Copenhagen, Denmark, Eye Clinic, University of Cologne, Joseph
Stelzmannstr. 9, D-50931 Cologne, Germany, and ** Department of
Molecular Toxicology, Faculty of Biology, University of Constance,
D-78457 Constance, Germany
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Institute of
Biochemistry, Swiss Federal Institute of Technology,
Universitätstr. 16, CH-8092 Zurich, Switzerland. Tel.:
41-1-6323021 or -6323136; Fax: 41-1-6321121; E-mail:
richter@bc.biol.ethz.ch.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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