MECHANISM OF ORGANELLE DEGRADATION IN THE LENS

晶状体纤维细胞的细胞核和细胞器在细胞分化过程中降解。因为光会被这些膜颗粒散射，所以这个过程对于清晰的视觉是必要的。人们对这种降解的生化和细胞机制及其调控知之甚少。类似的现象也发生在网织红细胞中，网织红细胞是红细胞的前体。排核后，包括线粒体和内质网在内的细胞器被降解。多年来，人们一直建议这个过程涉及脂氧合酶，这是一种双加氧酶，可以催化花生四烯酸和其他多烯脂肪酸的合成。已经提出了几种机制，都是基于脂氧合酶修饰细胞器膜脂类或膜相关蛋白。我们积累的数据支持一种全新的机制：我们提出，可溶性酶脂氧合酶组装成一个多聚体结构，在细胞器的膜上形成孔。这种小孔将允许细胞质蛋白质降解机制进入管腔，并启动细胞器的降解。我们还发现脂肪氧合酶在晶状体中表达，在周围纤维细胞中表达最强，那里发生了细胞核和细胞器的降解。我们假设，晶状体中的细胞器降解使用与网织红细胞相似的机制。这项提议将通过鉴定晶状体中表达的脂氧合酶同工酶，分析其表达的调节，更好地了解脂氧合酶如何透过细胞膜，以及研究脂氧合酶在动物模型和人类白内障晶状体中的表达来验证这一假说。

The nucleus and organelles of lens fiber cells are degraded during cell differentiation. Because light would be scattered by these membranous particles, this process is necessary for clear vision. Very little is known about the biochemical and cellular mechanisms of this degradation and their regulation. A similar phenomenon occurs in reticulocytes, precursors of red blood cells. Following nucleus expulsion, organelles, including mitochondria and endoplasmic reticulum, are degraded. It has been proposed for a number of years that this process involves lipoxygenase, an enzyme that dioxygenases arachidonic acid and other polyenoic fatty acids. Several mechanisms have been suggested, all based on lipoxygenase modifying organelle membrane lipids or membrane-associated proteins. We have accumulated data that support a totally new mechanism: we propose that the soluble enzyme lipoxygenase assembles into a multimeric structure that forms pores in the membranes of organelles. Such pores would allow the cytoplasmic protein degradation machinery to gain access to the lumenal compartment and initiate the degradation of the organelle. We also found that lipoxygenase is expressed in the lens, most strongly in the peripheral fiber cells where nucleus and organelle degradation occur. We hypothesize that organelle degradation in the lens uses a similar mechanism as in reticulocytes. This proposal will test this hypothesis by identifying the lipoxygenase isozyme expressed in lens, analyzing its regulation of expression, gaining a better understanding of how lipoxygenase permeates membranes, and studying the expression of lipoxygenase in animal model and human cataractous lenses.