Progeric effects of catalase inactivation in human cells.
Peroxisomes generate hydrogen peroxide, a reactive oxygen species, as part of their normal metabolism. A number of pathological situations exist in which the organelle's capacity to degrade the potentially toxic oxidant is compromised. It is the peroxidase, catalase, which largely determines the functional antioxidant capacity of the organelle, and it is this enzyme that is affected in aging, in certain diseases, and in response to exposure to specific chemical agents. To more tightly control the enzymatic activity of peroxisomal catalase and carefully document the effects of its impaired action on human cells, we employed the inhibitor 3-amino-1,2,4-triazole. We show that by chronically reducing catalase activity to approximately 38% of normal, cells respond in a dramatic manner, displaying a cascade of accelerated aging reactions. Hydrogen peroxide and related reactive oxygen species are produced, protein and DNA are oxidatively damaged, import into peroxisomes and organelle biogenesis is corrupted, and matrix metalloproteinases are hyper-secreted from cells. In addition, mitochondria are functionally impaired, losing their ability to maintain a membrane potential and synthesize reactive oxygen species themselves. These latter results suggest an important redox-regulated connection between the two organelle systems, a topic of considerable interest for future study.
Koepke
Jay I
JI
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Wood
Christopher S
CS
Terlecky
Laura J
LJ
Walton
Paul A
PA
Terlecky
Stanley R
SR
D000640:Amitrole / Q000494:pharmacology*; D002374:Catalase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000187:drug effects* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D000074435:Peroxisome-Targeting Signal 1 Receptor; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D006861:Hydrogen Peroxide; D002374:Catalase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D000640:Amitrole