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Solute Traffic Across the Mammalian Peroxisomal Membrane—The Role of Pxmp2

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Solute Traffic Across the Mammalian Peroxisomal Membrane—The Role of Pxmp2 A 517 OULU 2008 A 517 UNIVERSITY OF OULU P.O.B. 7500 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATISUNIVERSITATIS OULUENSISOULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTAACTA SERIES EDITORS SCIENTIAESCIENTIAEA A RERUMRERUM Aare Rokka NATURALIUMNATURALIUM ASCIENTIAE RERUM NATURALIUM Rokka Aare Professor Mikko Siponen SOLUTE TRAFFIC ACROSS BHUMANIORA THE MAMMALIAN University Lecturer Elise Kärkkäinen CTECHNICA PEROXISOMAL MEMBRANE Professor Hannu Heusala —THE ROLE OF PXMP2 DMEDICA Professor Olli Vuolteenaho ESCIENTIAE RERUM SOCIALIUM Senior Researcher Eila Estola FSCRIPTA ACADEMICA Information officer Tiina Pistokoski GOECONOMICA University Lecturer Seppo Eriksson EDITOR IN CHIEF Professor Olli Vuolteenaho PUBLICATIONS EDITOR Publications Editor Kirsti Nurkkala FACULTY OF SCIENCE, DEPARTMENT OF BIOCHEMISTRY, UNIVERSITY OF OULU; ISBN 978-951-42-8971-2 (Paperback) BIOCENTER OULU, ISBN 978-951-42-8972-9 (PDF) UNIVERSITY OF OULU ISSN 0355-3191 (Print) ISSN 1796-220X (Online) ACTA UNIVERSITATIS OULUENSIS A Scientiae Rerum Naturalium 517 AARE ROKKA SOLUTE TRAFFIC ACROSS THE MAMMALIAN PEROXISOMAL MEMBRANE—THE ROLE OF PXMP2 Academic dissertation to be presented, with the assent of the Faculty of Science of the University of Oulu, for public defence in Raahensali (Auditorium L10), Linnanmaa, on December 12th, 2008, at 12 noon OULUN YLIOPISTO, OULU 2008 Copyright © 2008 Acta Univ. Oul. A 517, 2008 Supervised by Professor Kalervo Hiltunen Professor Vasily Antonenkov Reviewed by Doctor Cécile Brocard Doctor Tiina Kotti ISBN 978-951-42-8971-2 (Paperback) ISBN 978-951-42-8972-9 (PDF) http://herkules.oulu.fi/isbn9789514289729/ ISSN 0355-3191 (Printed) ISSN 1796-220X (Online) http://herkules.oulu.fi/issn03553191/ Cover design Raimo Ahonen OULU UNIVERSITY PRESS OULU 2008 Rokka, Aare, Solute traffic across the mammalian peroxisomal membrane—the role of Pxmp2 Faculty of Science, Department of Biochemistry, University of Oulu, P.O.Box 3000, FI-90014 University of Oulu, Finland; Biocenter Oulu, University of Oulu, P.O. Box 5000, FI-90014 University of Oulu, Finland Acta Univ. Oul. A 517, 2008 Oulu, Finland Abstract Peroxisomes are small oxidative organelles found in all eukaryotes. They contain a matrix which is surrounded by a single membrane and consists mainly of soluble proteins. Peroxisomal enzymes are involved in a broad spectrum of metabolic pathways including conversion of lipids, amino- and hydroxyacids, purines and reactive oxygen species. The carbon fluxes through peroxisomal pathways require a continuous metabolite crossing of the peroxisomal membrane. A long-standing and still unresolved problem of the physiology of mammalian peroxisomes is the role of the membrane of these organelles as a permeability barrier to solute molecules. In this study, we have shown that the peroxisomal membrane represents a type of biomembrane where channel-forming proteins coexist with solute transporters. Disruption of the mouse Pxmp2 gene, encoding the peroxisomal integral membrane protein Pxmp2 also known as PMP22, leads to partial restriction of peroxisomal membrane permeability to solutes in vitro and in vivo. Multiple-channel recording of liver peroxisomal preparations revealed that the channel-forming components with a conductance of 1.3 nS in 1.0 M KCl were lost in Pxmp2-/- mice. The channel- forming properties of Pxmp2 were confirmed with recombinant protein expressed in insect cells and with native Pxmp2 purified from mouse liver. The Pxmp2 channel, with an estimated diameter of 1.4 nm, shows weak cation selectivity and no voltage dependence. The long-lasting open states of the channel indicate its functional role as a protein forming a general diffusion pore in the membrane. Hence, Pxmp2 is the first peroxisomal pore-forming protein identified, and its existence suggests that the mammalian peroxisomal membrane is permeable to small solutes, while transfer of bulky metabolites, e.g., cofactors (NAD/H, NADP/H, and CoA) and ATP, requires specific transporters. In addition, the phenotypic characterisation of Pxmp2-/- mice has revealed a role for Pxmp2 during the development of the epithelia in the mammary glands of female mice. The disruption of Pxmp2 leads to the impairment of ductal outgrowth of mammary glands at puberty, which is followed by the inability of Pxmp2-/- mice to nurse their offspring. Keywords: channel-forming proteins, mammary gland, peroxisomal membrane, Pxmp2 Acknowledgements This work was carried out at the Department of Biochemistry and Biocenter Oulu at the University of Oulu, Finland. I am deeply grateful to my supervisor Professor Kalervo Hiltunen for guiding me through the years to finally reach this goal. I would also like to thank my supervisor Professor Vasily Antonenkov for everything. This work would have never been accomplished without your effort and expertise. I owe my sincere thanks to Dr. Raija Soininen for her contribution to this work in generating and analysing the knock-out mouse model. I would like to thank the group leaders and staff at the department for creating a well functioning environment for research. I thank Dr. Tiina Kotti and Dr. Cécile Brocard for valuable comments on the thesis and Dr. Deborah Kaska for careful revision of the language. My deepest gratitude goes to all the people who have contributed to this work over the years. Especially, Dr. Raija Sormunen, Dr. Helmut Pospiech, Dr. Werner Schmitz, Dr. Päivi Pirilä, Dr. Ulrich Bergmann, Professor Roland Benz and Professor Matti Weckström are each acknowledged for providing their special expertise to this project. I am especially grateful to Miia Vapola whose contribution has been crucial for the finishing of this thesis work. I wish to thank Kalle, Jukka, Ilkka, Seppo, Dmitry, Tomi, Anu, Mari, Juha, Tiina, Tiila, Antti H., Hanna, Eija, Kristian, Alex, Miia, Samuli, François, Zhi-Jun, Kaija, Tatu, Maija, Antti I., Fumi, Tonja and all the other present and former members of the KH-group for companionship and support. Dr. Ari-Pekka Kvist deserves my thanks for helping me with computers, statistical analyses and other things. My special thanks go to Maija Risteli for guidance with insect cells. I thank Terttu Keskitalo, Hilkka Lehto and Katri Näppä for keeping my mice happy, Leena Ollitervo, Piia Mäkelä, Marika Kamps, Ville Ratas and Johanna Moilanen for excellent technical help, Anneli Kaattari, Pia Askonen and Tuula Koret for taking care of the official matters and Maire Jarva, Petra Heikkinen, Kyösti Keränen, Jaakko Keskitalo, Jari Karjalainen, Maila Konttila and Pirjo Mustaniemi for making everything work. The members of TOKU and Shellfish Graveyard are acknowledged for providing interesting experiences outside work. Finally, I want to thank my family members and parent in-laws. My warmest thanks belong to my wife Anu, who has managed to keep me on track to reach this destination. Without you it would have been impossible. 5 This work was supported by the Academy of Finland, Sigrid Juselius Foundation, Jenny and Antti Wihuri Foundation, Scientific Foundation of Instrumentarium and the FPG European Union Project “Peroxisome” (LSHG-CT- 2004-512018). Oulu, November 2008 Aare Rokka 6 Abbreviations ABC ATP-binding cassette ACOX acyl-CoA oxidase ALDP adrenoleukodystrophy protein ALDR adrenoleukodystrophy related protein AMP adenosine monophosphate ATP adenosine triphosphate cDNA complementary deoxyribonucleic acid CoA coenzyme A DHAP dihydroxyacetone phosphate DHCA 3α, 7α-dihydroxycholestanoic acid DNA deoxyribonucleic acid ER endoplasmic reticulum ES embryonic stem FAD flavine adenine dinucleotide kb kilobase kDa kilodalton LACS long-chain fatty acyl-CoA synthetase lacZ gene encoding β-galactosidase protein LCFA long-chain fatty acids LDH lactate dehydrogenase MCFA medium-chain fatty acids MCT monocarboxylate transporter MFE multifunctional enzyme NAD+ nicotinamide adenine dinucleotide NADP+ nicotinamide adenine dinucleotide phosphate PCR polymerase chain reaction PEX peroxin PGK phosphoglycerine kinase PMP peroxisomal membrane protein Pol DNA polymerase PTS peroxisomal targeting signal Pxmp2 22 kDa peroxisomal membrane protein RNA ribonucleic acid ROS reactive oxygen species SDS-PAGE sodium dodecyl sulphate polyacrylamide gel electrophoresis 7 THCA 3α, 7α, 12α-trihydroxycholestanoic acid UOX uric acid oxidase VDAC voltage-dependent anion channel VLACS very long-chain fatty acyl-CoA synthetase VLCFA very long-chain fatty acids X-ALD X-linked adrenoleukodystrophy 8 Contents Abstract Acknowledgements 5 Abbreviations 7 Contents 9 1 Introduction 11 2 Review of the literature 13 2.1 Peroxisomes ............................................................................................ 13 2.2 Peroxisomal biogenesis........................................................................... 13 2.3 Protein import into peroxisomes ............................................................. 14 2.3.1 Matrix protein import ................................................................... 14 2.3.2 Membrane protein import............................................................. 15 2.4 Peroxisomal metabolism......................................................................... 16 2.4.1 β-Oxidation................................................................................... 16 2.4.2 α-Oxidation................................................................................... 21 2.4.3 Polyamine oxidation..................................................................... 23 2.4.4 Ether phospholipid biosynthesis..................................................
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