Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells

Abstract

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.

Recovery of adriamycin induced mitochondrial dysfunction in liver by selenium

“…Although ROS may freely diffuse through intracellular membranes, subcellular compartmentalization of glutathione, an essential intracellular antioxidant, may significantly modulate the harmful activity of ROS in subcellular compartments (Dudka et al 2012). In a recent study, it was also shown that redox communication between peroxisomes and mitochondria may be important for ROS diffusion between subcellular compartments (Wang et al 2013). The liver due to the ADR metabolism may produce an important amount of ROS, but at the same time the antioxidant defence is a few times higher than, for example, that in the heart (Revis and Marusic 1978).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…We and others have shown that also disturbances in peroxisomal redox metabolism have an immediate impact on mitochondrial ROS production, both in cellulo (Walton and Pizzitelli, 2012;Wang et al, 2013b) and in vivo (López-Erauskin et al, 2013;Peeters et al, 2015). In addition, there is strong evidence that defects in peroxisome function as well as excessive ROS-production inside these organelles can trigger mitochondria-mediated cell death (López-Erauskin et al, 2012;Wang et al, 2013b). These and other findings clearly demonstrate that peroxisomal and mitochondrial fitness are closely intertwined, and-as such-it may not come as a surprise that both organelles play a cooperative role in the pathogenesis of at least some neurometabolic diseases.…”

“…In addition, it is becoming increasingly clear that mitochondria can act as dynamic receivers, integrators, and transmitters of oxidative stress derived from various sources (Nickel et al, 2014). We and others have shown that also disturbances in peroxisomal redox metabolism have an immediate impact on mitochondrial ROS production, both in cellulo (Walton and Pizzitelli, 2012;Wang et al, 2013b) and in vivo (López-Erauskin et al, 2013;Peeters et al, 2015). In addition, there is strong evidence that defects in peroxisome function as well as excessive ROS-production inside these organelles can trigger mitochondria-mediated cell death (López-Erauskin et al, 2012;Wang et al, 2013b).…”

“…As already mentioned above, SOD1 can convert O (Knoops et al, 2011). GSTK1 and MGST1 are thought to play a role in LOOH detoxification processes Johansson et al, 2010;Wang et al, 2013b), EPHX2 can convert epoxides to the corresponding dihydrodiols (Decker et al, 2009), and peroxisomal PRDX5 has recently been shown to exert a cytoprotective function against H 2 O 2 -and LOOH-induced oxidative stress (Walbrecq et al, 2015). For a detailed description of these enzymes, the reader is referred to other reviews .…”

“…•− 2 inside peroxisomes causes cellular lipid peroxidation, and that this in turn triggers a complex network of signaling events eventually resulting in increased mitochondrial H 2 O 2 production (Wang et al, 2013b). Note that, as (i) there is some evidence that the propagation of ROS signals from the ER to mitochondria is facilitated by membrane contact sites (Verfaillie et al, 2012), and (ii) such contact sites may also exist between peroxisomes and mitochondria (Horner et al, 2011;, it is possible that these sites are also involved in the redox communication between peroxisomes and mitochondria.…”