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Dissecting Peroxisome-Mediated Signaling Pathways: A New and Exciting Research Field

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Molecular Machines Involved in Peroxisome Biogenesis and Maintenance

Abstract

Peroxisomes are multifunctional organelles that play an important role in the metabolism of lipids and reactive oxygen species. As many cellular signaling functions are regulated via lipids, lipid second messengers, and oxidative stress-related factors, it is not surprising to see that these organelles are increasingly recognized as critical regulators of cellular signaling events. To fulfill these signaling functions, peroxisomes physically and functionally interact with other cell organelles, including mitochondria. Recent progress in the development of tools to visualize and modulate molecular processes at the subcellular level has made it possible to gain a better insight into the potential mechanisms governing peroxisomal signaling. This chapter is intended to provide a comprehensive overview of the tools and strategies that are currently available to study peroxisome-mediated signaling pathways in living cells. To provide the reader with relevant background information, we also highlight key studies that have contributed to our understanding of how peroxisomes may function as important sites of redox-, lipid-, inflammatory-, and viral-mediated signal transduction.

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References

  • Antonenkov VD, Grunau S, Ohlmeier S et al (2010) Peroxisomes are oxidative organelles. Antioxid Redox Signal 13:525–537

    Article  CAS  PubMed  Google Scholar 

  • Baarine M, Andréoletti P, Athias A et al (2012) Evidence of oxidative stress in very long chain fatty acid-treated oligodendrocytes and potentialization of ROS production using RNA interference-directed knockdown of ABCD1 and ACOX1 peroxisomal proteins. Neuroscience 213:1–18

    Article  CAS  PubMed  Google Scholar 

  • Barford D (2004) The role of cysteine residues as redox-sensitive regulatory switches. Curr Opin Struct Biol 14:679–686

    Article  CAS  PubMed  Google Scholar 

  • Beach A, Burstein MT, Richard VR et al (2012) Integration of peroxisomes into an endomembrane system that governs cellular aging. Front Physiol 3:283. doi:10.3389/fphys.2012.00283

    Article  PubMed Central  PubMed  Google Scholar 

  • Belousov VV, Fradkov AF, Lukyanov KA et al (2006) Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nat Methods 3:281–286

    Article  CAS  PubMed  Google Scholar 

  • Bikman BT, Summers SA (2011) Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 121:4222–4230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bottelbergs A, Verheijden S, Van Veldhoven PP et al (2012) Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system. J Neuroinflammation 9:61. doi:10.1186/1742-2094-9-61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128:617–630

    CAS  PubMed Central  PubMed  Google Scholar 

  • Braverman NE, Moser AB (2012) Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta 1822:1442–1452

    Article  CAS  PubMed  Google Scholar 

  • Brodde A, Teigler A, Brugger B et al (2012) Impaired neurotransmission in ether lipid-deficient nerve terminals. Hum Mol Genet 21:2713–2724

    Article  CAS  PubMed  Google Scholar 

  • Bulina ME, Chudakov DM, Britanova OV et al (2006) A genetically encoded photosensitizer. Nat Biotechnol 24:95–99

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Jiang Z (2013) The essential adaptors of innate immune signaling. Protein Cell 4:27–39

    Article  CAS  PubMed  Google Scholar 

  • Chen ZH, Niki E (2006) 4-hydroxynonenal (4-HNE) has been widely accepted as an inducer of oxidative stress. Is this the whole truth about it or can 4-HNE also exert protective effects? IUBMB Life 58:372–373

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Liang H, Van Remmen H et al (2004) Catalase transgenic mice: characterization and sensitivity to oxidative stress. Arch Biochem Biophys 422:197–210

    Article  CAS  PubMed  Google Scholar 

  • Chudakov DM, Matz MV, Lukyanov S et al (2010) Fluorescent proteins and their applications in imaging living cells and tissues. Physiol Rev 90:1103–1163

    Article  CAS  PubMed  Google Scholar 

  • Costa A, Drago I, Behera S et al (2010) H2O2 in plant peroxisomes: an in vivo analysis uncovers a Ca2+-dependent scavenging system. Plant J 62:760–772

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dansen TB, Wirtz KW (2001) The peroxisome in oxidative stress. IUBMB Life 51:223–230

    Article  CAS  PubMed  Google Scholar 

  • Dansen TB, Wirtz KW, Wanders RJ et al (2000) Peroxisomes in human fibroblasts have a basic pH. Nat Cell Biol 2:51–53

    Article  CAS  PubMed  Google Scholar 

  • Del Río LA (2011) Peroxisomes as a cellular source of reactive nitrogen species signal molecules. Arch Biochem Biophys 506:1–11

    Article  PubMed  Google Scholar 

  • Delille HK, Agricola B, Guimaraes SC et al (2010) Pex11pbeta-mediated growth and division of mammalian peroxisomes follows a maturation pathway. J Cell Sci 123:2750–2762

    Article  CAS  PubMed  Google Scholar 

  • Diano S, Liu ZW, Jeong JK et al (2011) Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med 17:1121–1127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dikalov S, Griendling KK, Harrison DG (2007) Measurement of reactive oxygen species in cardiovascular studies. Hypertension 49:717–727

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dixit E, Boulant S, Zhang Y et al (2010) Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141:668–681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doulias PT, Tenopoulou M, Greene JL et al (2013) Nitric oxide regulates mitochondrial fatty acid metabolism through reversible protein S-nitrosylation. Sci Signal 6(256):rs1. doi:10.1126/scisignal.2003252

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Drago I, Giacomello M, Pizzo P et al (2008) Calcium dynamics in the peroxisomal lumen of living cells. J Biol Chem 283:14384–14390

    Article  CAS  PubMed  Google Scholar 

  • El Hajj HI, Vluggens A, Andreoletti P et al (2012) The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy). Endocrinology 153:2568–2575

    Article  PubMed Central  PubMed  Google Scholar 

  • Elsner M, Gehrmann W, Lenzen S (2011) Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells. Diabetes 60:200–208

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fourcade S, López-Erauskin J, Galino J et al (2008) Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum Mol Genet 17:1762–1773

    Article  CAS  PubMed  Google Scholar 

  • Fransen M (2012) Peroxisome dynamics: molecular players, mechanisms, and (dys)functions. ISRN Cell Biol article ID 714192. doi:10.5402/2012/714192

  • Fransen M, Nordgren M, Wang B et al (2012) Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim Biophys Acta 1822:1363–1373

    Article  CAS  PubMed  Google Scholar 

  • Fransen M, Nordgren M, Wang B et al (2013) Aging, age-related diseases and peroxisomes. Subcell Biochem 69:45–65

    Article  CAS  PubMed  Google Scholar 

  • Gutscher M, Sobotta MC, Wabnitz GH et al (2009) Proximity-based protein thiol oxidation by H2O2-scavenging peroxidases. J Biol Chem 284:31532–31540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Halvey PJ, Hansen JM, Johnson JM et al (2007) Selective oxidative stress in cell nuclei by nuclear-targeted D-amino acid oxidase. Antioxid Redox Signal 9:807–816

    Article  CAS  PubMed  Google Scholar 

  • Hanson GT, Aggeler R, Oglesbee D et al (2004) Investigating mitochondrial redox potential with redox-sensitive green fluorescent protein indicators. J Biol Chem 279:13044–13053

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa K, Wakino S, Yoshioka K et al (2010) Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 285:13045–13056

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hori Y, Kikuchi K (2013) Protein labeling with fluorogenic probes for no-wash live-cell imaging of proteins. Curr Opin Chem Biol 17:644–650

    Article  CAS  PubMed  Google Scholar 

  • Horner SM, Liu HM, Park HS et al (2011) Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc Natl Acad Sci USA 108:14590–14595

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Huybrechts SJ, Van Veldhoven PP, Brees C et al (2009) Peroxisome dynamics in cultured mammalian cells. Traffic 10:1722–1733

    Article  CAS  PubMed  Google Scholar 

  • Hwang I, Lee J, Huh JY et al (2012) Catalase deficiency accelerates diabetic renal injury through peroxisomal dysfunction. Diabetes 61:728–738

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ivashchenko O, Van Veldhoven PP, Brees C et al (2011) Intraperoxisomal redox balance in mammalian cells: oxidative stress and interorganellar cross-talk. Mol Biol Cell 22:1440–1451

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jankowski A, Kim JH, Collins RF et al (2001) In situ measurements of the pH of mammalian peroxisomes using the fluorescent protein pHluorin. J Biol Chem 276:48748–48753

    Article  CAS  PubMed  Google Scholar 

  • Karlsson M, Kurz T, Brunk UT et al (2010) What does the commonly used DCF test for oxidative stress really show? Biochem J 428:183–190

    Article  CAS  PubMed  Google Scholar 

  • Kasai H, Okada Y, Nishimura S et al (1989) Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator. Cancer Res 49:2603–2605

    CAS  PubMed  Google Scholar 

  • Kassmann CM, Lappe-Siefke C, Baes M et al (2007) Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet 39:969–976

    Article  CAS  PubMed  Google Scholar 

  • Kim PK, Mullen RT, Schumann U et al (2006) The origin and maintenance of mammalian peroxisomes involves a de novo PEX16-dependent pathway from the ER. J Cell Biol 173:521–532

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kojima H, Urano Y, Kikuchi K et al (1999) Fluorescent indicators for imaging nitric oxide. Angew Chem Int Ed Eng 38:3209–3212

    Article  CAS  Google Scholar 

  • Kozawa S, Honda A, Kajiwara N et al (2011) Induction of peroxisomal lipid metabolism in mice fed a high-fat diet. Mol Med Rep 4:1157–1162

    CAS  PubMed  Google Scholar 

  • Lasorsa FM, Pinton P, Palmieri L et al (2008) Peroxisomes as novel players in cell calcium homeostasis. J Biol Chem 283:15300–15308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lazarow PB (2011) Viruses exploiting peroxisomes. Curr Opin Microbiol 14:458–469

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Tharappel JC, Cooper S et al (2000) Expression of the hydrogen peroxide-generating enzyme fatty acyl CoA oxidase activates NF-kappaB. DNA Cell Biol 19:113–120

    Article  PubMed  Google Scholar 

  • Li Y, Chen R, Zhou Q et al (2012) LSm14A is a processing body-associated sensor of viral nucleic acids that initiates cellular antiviral response in the early phase of viral infection. Proc Natl Acad Sci USA 109:11770–11775

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Los GV, Encell LP, McDougall MG et al (2008) HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem Biol 3:373–382

    Article  CAS  PubMed  Google Scholar 

  • Lukyanov KA, Belousov VV (2013) Genetically encoded fluorescent redox sensors. Biochim Biophys Acta. doi:10.1016/j.bbagen.2013.05.030

    Google Scholar 

  • Mast FD, Li J, Virk MK et al (2011) A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders. Dis Model Mech 4:659–672

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miesenböck G, De Angelis DA, Rothman JE (1998) Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394:192–195

    Article  PubMed  Google Scholar 

  • Müller CC, Nguyen TH, Ahlemeyer B et al (2011) PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress. Dis Model Mech 4:104–119

    Article  PubMed Central  PubMed  Google Scholar 

  • Nagano T (2009) Bioimaging probes for reactive oxygen species and reactive nitrogen species. J Clin Biochem Nutr 45:111–124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palmer AE, Giacomello M, Kortemme T et al (2006) Ca2+ indicators based on computationally redesigned calmodulin-peptide pairs. Chem Biol 13:521–530

    Article  CAS  PubMed  Google Scholar 

  • Pettus BJ, Baes M, Busman M et al (2004) Mass spectrometric analysis of ceramide perturbations in brain and fibroblasts of mice and human patients with peroxisomal disorders. Rapid Commun Mass Spectrom 18:1569–1574

    Article  CAS  PubMed  Google Scholar 

  • Rhodin J (1954) Correlation of ultrastructural organization and function in normal and experimentally changed proximal tubule cells of the mouse kidney. Dissertation, Karolinska Institutet

    Google Scholar 

  • Ribeiro D, Castro I, Fahimi HD et al (2012) Peroxisome morphology in pathology. Histol Histopathol 27:661–676

    CAS  PubMed  Google Scholar 

  • Rizzuto R, Simpson AW, Brini M et al (1992) Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature 358:325–327

    Article  CAS  PubMed  Google Scholar 

  • Schwarzländer M, Fricker MD, Müller C et al (2008) Confocal imaging of glutathione redox potential in living plant cells. J Microsc 231:299–316

    Article  PubMed  Google Scholar 

  • Singh J, Khan M, Singh I (2009) Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy. J Lipid Res 50:135–147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Soardo G, Donnini D, Domenis L et al (2011) Oxidative stress is activated by free fatty acids in cultured human hepatocytes. Metab Syndr Relat Disord 9:397–401

    Article  CAS  PubMed  Google Scholar 

  • Stolz DB, Zamora R, Vodovotz Y et al (2002) Peroxisomal localization of inducible nitric oxide synthase in hepatocytes. Hepatology 36:81–93

    Article  CAS  PubMed  Google Scholar 

  • Swietach P, Youm JB, Saegusa N et al (2013) Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling. Proc Natl Acad Sci USA 110:E2064–E2073

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tantama M, Hung YP, Yellen G (2011) Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor. J Am Chem Soc 133:10034–10037

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Titorenko VI, Terlecky SR (2011) Peroxisome metabolism and cellular aging. Traffic 12:252–259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Van Veldhoven PP (2010) Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res 51:2863–2895

    Article  PubMed Central  PubMed  Google Scholar 

  • Vasko R, Ratliff BB, Bohr S et al (2013) Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury. Antioxid Redox Signal 19:211–230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Verheijden S, Bottelbergs A, Krysko O et al (2013) Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation. Neurobiol Dis 58:258–269

    Article  CAS  PubMed  Google Scholar 

  • Wahli W, Michalik L (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 23:351–363

    Article  CAS  PubMed  Google Scholar 

  • Walton PA, Pizzitelli M (2012) Effects of peroxisomal catalase inhibition on mitochondrial function. Front Physiol 3:108. doi:10.3389/fphys.2012.00108

    Article  PubMed Central  PubMed  Google Scholar 

  • Wang S, Li N, Pan W et al (2012) Advances in functional fluorescent and luminescent probes for imaging intracellular small-molecule reactive species. Trend Anal Chem 39:3–37

    Article  Google Scholar 

  • Yang Y, Song Y, Loscalzo J (2007) Regulation of the protein disulfide proteome by mitochondria in mammalian cells. Proc Natl Acad Sci USA 104:10813–10817

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yano T, Oku M, Akeyama N et al (2010) A novel fluorescent sensor protein for visualization of redox states in the cytoplasm and in peroxisomes. Mol Cell Biol 30:3758–3766

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang J, Kim J, Alexander A et al (2013) A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat Cell Biol 15:1186–1196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

MF is supported by grants from the “Fonds voor Wetenschappelijk Onderzoek- Vlaanderen (Onderzoeksproject G.0754.09)” and the “Bijzonder Onderzoeksfonds van de KU Leuven (OT/09/045).” MN is supported by a FLOF fellowship from the Department of Cellular and Molecular Medicine, KU Leuven. BW is a recipient of a DBOF fellowship (DBOF/10/059) from the KU Leuven.

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Correspondence to Marc Fransen .

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Wang, B., Apanasets, O., Nordgren, M., Fransen, M. (2014). Dissecting Peroxisome-Mediated Signaling Pathways: A New and Exciting Research Field. In: Brocard, C., Hartig, A. (eds) Molecular Machines Involved in Peroxisome Biogenesis and Maintenance. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1788-0_11

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