Inhibition of peroxisomal functions due to oxidative imbalance induced by mistargeting of catalase to cytoplasm is restored by vitamin E treatment in skin fibroblasts from Zellweger syndrome-like patients

Abstract

Many of the peroxisomal diseases exhibit excessive oxidative stress leading to neurological alterations and dysfunction. The role of peroxisomal oxidative stress in cellular function was highlighted by the loss of metabolic functions in peroxisomes of mutant cell lines, where catalase is mistargeted to the cytoplasm, but restored to peroxisomes by genetic manipulation (Sheikh et al. [Proc. Natl. Acad. Sci. USA 95 (1998) 2961)]. We report here that two human skin fibroblast cell lines from Zellweger syndrome-like patients are defective in the import of catalase into peroxisomes, causing impairment of metabolic function of this organelle. However, by lowering the cell culturing temperature (30 °C) the targeting of catalase to peroxisomes was restored, and with it the metabolic functions. Furthermore, mislocalization of catalase induces an oxidative imbalance in the cells which on treatment with a natural antioxidant, α-tocopherol (vitamin E), resulted in reduction of the oxidative levels and restoration of metabolic function (peroxisomal β-oxidation and levels of very long chain fatty acids and plasmalogen as well as α-oxidation of branched-chain fatty acids). However, restoration of peroxisomal functions was not associated with the targeting of catalase to peroxisomes. Therefore, our finding suggests that correction of mistargeted catalase to peroxisomes is a temperature sensitive event and supports the hypotheses that its location outside peroxisomes induces an oxidative imbalance that results in metabolic dysfunction. The imbalance can be reversed by treatment with vitamin E, leading to normalization of peroxisomal functions. These findings open a novel approach for therapeutic treatment of certain peroxisomal disorders where gene or hypothermic therapies are not an option.