Peroxisome senescence and the role of catalase import in cellular aging
Peroxisomes are ubiquitous subcellular organelles required for proper functioning of eukaryotic cells. They efficiently compartmentalize enzymes responsible for a number of essential cellular processes, including the metabolism of certain specific fatty acid chains via 13-oxidation. These and other oxidative reactions produce hydrogen peroxide, which is, in most instances, immediately processed in situ to water and oxygen. The responsible peroxidase is the heme-containing tetrameric enzyme, catalase. What has emerged during our investigation is that there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset - leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific xenobiotics. Our results indicate that the import of peroxisomal proteins containing a type 1 targeting signal (PTS1) decline with age in human diploid fibroblasts. Compromised to an even greater extent is the import of catalase - an enzyme with a poorly recognized PTS1. Taken together, these data suggest that as cells age, the ability to maintain a balance of hydrogen peroxide-generating and - degrading activities within peroxisomes is disrupted. This leads to peroxisomal dysfunction, which increases the oxidative load experienced by cells and presumably contributes to the aging process. The overall goal of this thesis is to describe the molecular events associated with the development and advancement of peroxisomal senescence and to describe its effects on cells. In addition, results of these efforts to increase levels of peroxisomal catalase and restore oxidative balance in cells.