View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1822 (2012) 1363–1373 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review Role of peroxisomes in ROS/RNS-metabolism: Implications for human disease☆ Marc Fransen ⁎, Marcus Nordgren, Bo Wang, Oksana Apanasets Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49 box 601, B-3000 Leuven, Belgium article info abstract Article history: Peroxisomes are cell organelles that play a central role in lipid metabolism. At the same time, these organelles Received 30 September 2011 generate reactive oxygen and nitrogen species as byproducts. Peroxisomes also possess intricate protective Received in revised form 25 November 2011 mechanisms to counteract oxidative stress and maintain redox balance. An imbalance between peroxisomal Accepted 2 December 2011 reactive oxygen species/reactive nitrogen species production and removal may possibly damage biomole- Available online 9 December 2011 cules, perturb cellular thiol levels, and deregulate cellular signaling pathways implicated in a variety of human diseases. Somewhat surprisingly, the potential role of peroxisomes in cellular redox metabolism Keywords: Peroxisome has been underestimated for a long time. However, in recent years, peroxisomal reactive oxygen species/ Oxidative stress reactive nitrogen species metabolism and signaling have become the focus of a rapidly evolving and multidis- Antioxidant ciplinary research field with great prospects. This review is mainly devoted to discuss evidence supporting Redox signaling the notion that peroxisomal metabolism and oxidative stress are intimately interconnected and associated Interorganellar crosstalk with age-related diseases. We focus on several key aspects of how peroxisomes contribute to cellular reactive Age-related disease oxygen species/reactive nitrogen species levels in mammalian cells and how these cells cope with peroxisome-derived oxidative stress. We also provide a brief overview of recent strategies that have been successfully employed to detect and modulate the peroxisomal redox status. Finally, we highlight some gaps in our knowledge and propose potential avenues for further research. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease. © 2011 Elsevier B.V. All rights reserved. 1. Introduction depends on the site, type, and amount of ROS/RNS production and the activity of the organism's antioxidant defense system [7]. Over the past decades, free radicals and other reactive small mol- Endogenous ROS/RNS can be generated as the primary function of ecules have emerged as important regulators of many physiological an enzyme system (e.g. NADPH oxidases that are activated in response and pathological processes [1,2]. Currently, it is well established to activated receptors), as a byproduct of other biological reactions (e.g. that – at physiological low levels – reactive oxygen species (ROS) the mitochondrial electron transport chain), or by metal-catalyzed oxi- 2+ 3+ − and reactive nitrogen species (RNS) serve as signaling messengers dations (e.g. the Fenton reaction: Fe +H2O2 →Fe +•OH+ OH) to mediate various biological responses, including gene expression, [8]. The primary ROS/RNS species generated in a cell are superoxide − cell proliferation, angiogenesis, innate immunity, programmed cell (O2• ), hydrogen peroxide (H2O2), and nitric oxide (NO•) [2].These death, and senescence [3,4]. On the other hand, it is also known that molecules can readily react to form other ROS and RNS species. For ex- − − increased levels of these short-lived reactive molecules can exert ample, O2• can rapidly react with NO• to form peroxynitrite (ONOO ) harmful effects by causing oxidative damage to biological macromol- or dismutate to form H2O2, and the latter compound can be decom- ecules and disrupting the cellular reduction–oxidation (redox) bal- posed through the Fenton reaction leading to the generation of hydrox- ance [3,5]. A disturbance of ROS/RNS homeostasis is generally yl radicals (•OH) [8]. considered as a risk factor for the initiation and progression of dis- To counteract oxidative and nitrosative stress, cells employ a large eases such as atherosclerosis, diabetes, neurodegeneration, and can- panel of enzymatic and non-enzymatic defense mechanisms [8]. cer [5,6]. Whether the effects of ROS/RNS are beneficial or harmful Stress occurs when the net flux of ROS/RNS production exceeds the Abbreviations: 3-AT, 3-Amino-1,2,4-triazole; CFP, cyan fluorescent protein; EC number, Enzyme Commission number; ER, endoplasmic reticulum; FAO, fatty acyl-CoA oxidase; FRET, fluorescence resonance energy transfer; GSH, reduced glutathione; GSSG, oxidized glutathione; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; PPARα, peroxisome proliferator-activated receptor alpha; PTS, peroxisomal targeting signal; PTS1, C-terminal peroxisomal targeting signal; RNS, reactive nitrogen species; roGFP, redox-sensitive green fluorescent protein; ROS, reactive oxygen species; YFP, yellow fluorescent protein ☆ This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease. ⁎ Corresponding author. Tel.: +32 16 330114; fax: +32 16 330642. E-mail address: [email protected] (M. Fransen). 0925-4439/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2011.12.001 1364 M. Fransen et al. / Biochimica et Biophysica Acta 1822 (2012) 1363–1373 capacity of the cell to detoxify these potentially injurious oxidants [9]. oxidation, and the oxidative part of the pentose phosphate pathway It is often assumed that mitochondria are the primary source of oxi- [30]. Interestingly, many of the enzymes participating in these path- dative stress in mammalian cells [10]. However, there is currently ways generate specific ROS or RNS as byproducts of their normal cat- no convincing experimental evidence to support this postulate [11]. alytic function (Table 1) [31]. In this section, we will focus on the In addition, the only currently available study comparing the relative different types of ROS/RNS that can be generated inside peroxisomes. ROS production by different cellular sources demonstrated that the endoplasmic reticulum (ER) and peroxisomes may even have a great- 2.1.1. Hydrogen peroxide er capacity to produce ROS than mitochondria, at least in rat liver Peroxisomes contain various enzymes that produce H2O2 as part of [12]. Research efforts on ER-generated oxidative stress have revealed their normal catalytic cycle. These enzymes, which are mainly flavopro- that the production of ROS is closely linked to protein folding [13]. teins, include acyl-CoA oxidases, urate oxidase, D-amino acid oxidase, Furthermore, it has been shown that chronic ER-derived oxidative D-aspartate oxidase, L-pipecolic acid oxidase, L-α-hydroxyacid oxidase, stress plays a critical role in the initiation of apoptosis and the patho- polyamine oxidase, and xanthine oxidase. For a detailed description of genesis of multiple metabolic and neurodegenerative diseases [14]. these enzymes, we refer to an excellent recent review covering this Surprisingly, for a long time, little attention was paid to the impor- topic [31]. tance of peroxisomes in cellular ROS/RNS homeostasis. However, in recent years, peroxisomal ROS/RNS metabolism and signaling has be- 2.1.2. Superoxide- and nitric oxide radicals − come an exciting and rapidly evolving multidisciplinary research field Peroxisomes contain two potential enzymatic sources of O2• and [15–17]. In this review, we will provide an overview of our current NO•, namely xanthine oxidase and the inducible form of nitric oxide knowledge on how peroxisomes contribute to the maintenance of synthase. Xanthine oxidase (XDH) is an enzyme that produces H2O2 − cellular ROS/RNS levels and how cells cope with peroxisome- (see Section 2.1.1.) and O2• as byproducts of its catalytic cycle [32]. derived oxidative stress. In addition, we will highlight the present In addition, this enzyme can also reduce nitrates and nitrites to NO• gaps in our knowledge and outline a set of strategies that can drive [33]. The inducible form of nitric oxide synthase (NOS2) is a homodi- this research field forward. Note that we will mainly focus on mam- meric enzyme that catalyzes the oxidation of L-arginine to NO• and cit- malian peroxisomes, although it should be emphasized that a signifi- rulline in a complex reaction requiring O2, NADPH, tetrahydrobiopterin cant portion of the pioneering work in this area was carried out in (BH4), FMN, and FAD [16]. Interestingly, in the absence of adequate other organisms such as yeasts [18], nematodes [19], and plants [16]. substrate or when in its monomeric form, the enzyme can also produce − significant amounts of O2• [34]. The precise subcellular localization of 2. Peroxisomal ROS/RNS metabolism NOS2 remains enigmatic and can vary depending on the cell type and the environment of the cell [35]. Localization studies of NOS2 have The term ‘peroxisome’ was introduced by Nobel Laureate Christian shown that this protein displays a dual cytosolic-peroxisomal localiza- de Duve in 1965 to define a cell organelle which contains at least tion in hepatocytes