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
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
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DOI：
10.1074/jbc.m007049200
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发表时间：
2000-12-15
影响因子：
4.8
通讯作者：
Richter, C
中科院分区：
文献类型：
--
作者：
Suter, M;Remé, C;Richter, C
在65岁以上的人群中，有10%-20%的人患有老年性黄斑变性(ARID)，这是发达国家人类严重视力障碍的主要原因，这种复杂疾病的发病机制尚不清楚，到目前为止还没有有效的治疗或预防措施。视网膜色素上皮(RPE)细胞溶酶体中AGE色素脂褐素的积聚可能是视网膜色素上皮(RPE)细胞发生ARD的先决条件。在AMD中，这些细胞似乎是通过凋亡而死亡的，随后感光细胞也会死亡，而光可能会加速疾病的进程。导致细胞死亡的细胞内因素尚不清楚。在这里，我们展示了脂褐素成分的亲脂性阳离子N-视黄基-N-视黄醇乙醇胺(A2E)在人视网膜中发现的浓度诱导RPE和其他细胞凋亡。细胞凋亡伴随着促凋亡蛋白细胞色素c和凋亡诱导因子在细胞质和细胞核中的出现。生化检测表明，A2E特异性靶向细胞色素氧化酶(COX)。对于分离的线粒体和纯化的COX，A2E与光协同抑制氧消耗。细胞色素c或心磷脂(一种带负电荷的磷脂，促进细胞色素c与细胞膜的结合)的抑制作用可被逆转，琥珀酸脱氢酶的活性不被A2E改变。我们认为A2E可能通过线粒体相关的机制作为促凋亡分子，可能通过位置特异性地将这种阳离子靶向COX。通过抑制线粒体功能而丧失RPE细胞的活力可能是导致中央视网膜进行性退化的关键步骤。
10-20% of individuals over the age of 65 suffer hom age-related macular degeneration (ARID), 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 ARID 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.