Peroxisomes as Modulators of Cellular Protein Thiol Oxidation: A New Model System

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Aims: Peroxisomes are ubiquitous, single-membrane-bounded organelles that contain considerable amounts of enzymes involved in the production or breakdown of hydrogen peroxide (H 2 O 2 ), a key signaling molecule in multiple biological processes and disease states. Despite this, the role of this organelle in cross-compartmental H 2 O 2 signaling remains largely unclear, mainly because of the difficulty to modulate peroxisomal H 2 O 2 production in a selective manner. This study aimed at establishing and validating a cellular model suitable to decipher the complex signaling processes associated with peroxisomal H 2 O 2 release. Results: Here, we report the development of a human cell line that can be used to selectively generate H 2 O 2 inside peroxisomes in a time- and dose-controlled manner. In addition, we provide evidence that peroxisome-derived H 2 O 2 can oxidize redox-sensitive cysteine residues in multiple proteins within ( e.g. , peroxiredoxin-5 [PRDX5]) and outside ( e.g. , nuclear factor kappa B subunit 1 [NFKB1] and subunit RELA proto-oncogene [RELA], phosphatase and tensin homolog [PTEN], forkhead box O3 [FOXO3], and peroxin 5 [PEX5]) the peroxisomal compartment. Furthermore, we show that the extent of protein oxidation depends on the subcellular location of the target protein and is inversely correlated to catalase activity and cellular glutathione content. Finally, we demonstrate that excessive H 2 O 2 production inside peroxisomes does not induce their selective degradation, at least not under the conditions examined. Innovation: This study describes for the first time a powerful model system that can be used to examine the role of peroxisome-derived H 2 O 2 in redox-regulated (patho)physiological processes, a research area in need of further investigation and innovative approaches. Conclusion: Our results provide unambiguous evidence that peroxisomes can serve as regulatory hubs in thiol-based signaling networks.

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