Suter M, Remé C, Grimm C, Wenzel A, Jäättela M, Esser P, Kociok N, Leist M, Richter C
Institute of Biochemistry, Swiss Federal Institute of Technology, Universitätstr. 16, CH-8092 Zurich, Switzerland.
J Biol Chem. 2000 Dec 15;275(50):39625-30. doi: 10.1074/jbc.M007049200.
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.
65岁以上的人群中，有10% - 20%患有年龄相关性黄斑变性（AMD），这是发达国家人群严重视力损害的主要原因。这种复杂疾病的发病机制尚不清楚，迄今为止也没有有效的治疗方法或预防措施。AMD的一个先决条件似乎是视网膜色素上皮（RPE）细胞溶酶体中衰老色素脂褐质的积累。在AMD中，这些细胞似乎通过凋亡死亡，随后光感受器细胞也死亡，并且光可能加速疾病进程。导致细胞死亡的细胞内因素尚不清楚。在此我们表明，脂溶性阳离子N - 视黄基 - N - 视黄叉乙醇胺（A2E），一种脂褐质成分，在人视网膜中发现的浓度下可诱导RPE细胞和其他细胞凋亡。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与光协同抑制氧气消耗。添加细胞色素c或心磷脂（一种促进细胞色素c与膜结合的带负电荷的磷脂）可逆转这种抑制作用。琥珀酸脱氢酶活性不受A2E影响。我们认为，A2E可能通过与线粒体相关的机制作为一种促凋亡分子发挥作用，可能是通过该阳离子对COX的位点特异性靶向。通过抑制线粒体功能导致RPE细胞活力丧失可能是中央视网膜进行性退变的关键步骤。
