Many cellular processes are driven by spatially and temporally regulated redox-dependent signaling events. Although mounting evidence indicates that organelles such as the endoplasmic reticulum and mitochondria can function as signaling platforms for oxidative stress-regulated pathways, little is known about the role of peroxisomes in these processes. In this study, we employ targeted variants of the genetically encoded photosensitizer KillerRed to gain a better insight into the interplay between peroxisomes and cellular oxidative stress. We show that the phototoxic effects of peroxisomal KillerRed induce mitochondria-mediated cell death and that this process can be counteracted by targeted overexpression of a select set of antioxidant enzymes, including peroxisomal glutathione S-transferase kappa 1, superoxide dismutase 1, and mitochondrial catalase. We also present evidence that peroxisomal disease cell lines deficient in plasmalogen biosynthesis or peroxisome assembly are more sensitive to KillerRed-induced oxidative stress than control cells. Collectively, these findings confirm and extend previous observations suggesting that disturbances in peroxisomal redox control and metabolism can sensitize cells to oxidative stress. In addition, they lend strong support to the ideas that peroxisomes and mitochondria share a redox-sensitive relationship and that the redox communication between these organelles is not only mediated by diffusion of reactive oxygen species from one compartment to the other. Finally, these findings indicate that mitochondria may act as dynamic receivers, integrators, and transmitters of peroxisome-derived mediators of oxidative stress, and this may have profound implications for our views on cellular aging and age-related diseases.
Keywords: ALS; CAT; Cell death; ER; Free radicals; GSTK1; HuF; KR; KillerRed; LA; Lipid peroxidation; MEF; Mitochondria; N-acetylcysteine; NAC; Organelle cross-talk; Oxidative stress; PARP; Peroxisomes; RIPK1; ROS; Redox signaling; SOD1; amyotrophic lateral sclerosis; c; catalase; cytosolic; endoplasmic reticulum; glutathione S-transferase kappa 1; human fibroblast; mitochondrial; mouse embryonic fibroblast; mt; peroxisomal; po; poly(ADP-ribose) polymerase; reactive oxygen species; receptor-interacting protein kinase 1; superoxide dismutase 1; α-lipoic acid.
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