MECHANISM OF ORGANELLE DEGRADATION IN THE LENS

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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.