Restoration of Peroxisomal Catalase Import in a Model of Human Cellular Aging

Abstract

Peroxisomes play an important role in human cellular metabolism by housing enzymes involved in a number of essential biochemical pathways. Many of these enzymes are oxidases that transfer hydrogen atoms to molecular oxygen forming hydrogen peroxide. The organelle also contains catalase, which readily decomposes the hydrogen peroxide, a potentially damaging oxidant. Previous work has demonstrated that aging compromises peroxisomal protein import with catalase being particularly affected. The resultant imbalance in the relative ratio of oxidases to catalase was seen as a potential contributor to cellular oxidative stress and aging. Here we report that altering the peroxisomal targeting signal of catalase to the more effective serine-lysine-leucine (SKL) sequence results in a catalase molecule that more strongly interacts with its receptor and is more efficiently imported in both in vitro and in vivo assays. Furthermore, catalase-SKL monomers expressed in cells interact with endogenous catalase subunits resulting in altered trafficking of the latter molecules. A dramatic reduction in cellular hydrogen peroxide levels accompanies this increased peroxisomal import of catalase. Finally, we show that catalase-SKL stably expressed in cells by retroviral-mediated transduction repolarizes mitochondria and reduces the number of senescent cells in a population. These results demonstrate the utility of a catalase-SKL therapy for the restoration of a normal oxidative state in aging cells.