BBA - Molecular Cell Research (v.1763, #12)
Editorial Board (ii).
Introduction: Peroxisomes by Wolf Kunau (1363).
Yeast and filamentous fungi as model organisms in microbody research by Ida J. van der Klei; Marten Veenhuis (1364-1373).
Yeast and filamentous fungi are important model organisms in microbody research. The value of these organisms as models for higher eukaryotes is underscored by the observation that the principles of various aspects of microbody biology are strongly conserved from lower to higher eukaryotes. This has allowed to resolve various peroxisome-related functions, including peroxisome biogenesis disorders in man. This paper summarizes the major advances in microbody research using fungal systems and specifies specific properties and advantages/disadvantages of the major model organisms currently in use.
Keywords: Peroxisome; Glyoxysome; Hydrogenosome; Yeast; PEX gene; Pexophagy; Woronin body;
Lessons from peroxisome-deficient Chinese hamster ovary (CHO) cell mutants by Yukio Fujiki; Kanji Okumoto; Naohiko Kinoshita; Kamran Ghaedi (1374-1381).
Cells with a genetic defect affecting a biological activity and/or a cell phenotype are generally called “cell mutants” and are a highly useful tool in genetic, biochemical, as well as cell biological research. To investigate peroxisome biogenesis and human peroxisome biogenesis disorders, more than a dozen complementation groups of Chinese hamster ovary (CHO) cell mutants defective in peroxisome assembly have been successfully isolated and established as a model system. Moreover, successful PEX gene cloning studies by taking advantage of rapid functional complementation assay of CHO cell mutants invaluably contributed to the accomplishment of isolation of pathogenic genes responsible for peroxisome biogenesis diseases. Molecular mechanisms of peroxisome assembly are currently investigated by making use of such mammalian cell mutants.
Keywords: CHO cell mutant; Genetic phenotype-complementation; Peroxin; Peroxisome ghost; Zellweger syndrome; Patients' fibroblast; Pathogenic gene;
Arabidopsis thaliana—A model organism to study plant peroxisomes by Makoto Hayashi; Mikio Nishimura (1382-1391).
In higher plants, peroxisomes have been believed to play a pivotal role in three metabolic pathways, which are lipid breakdown, photorespiration and H2O2-detoxificaton. Recently, significant progress in the study of plant peroxisomes was established by forward-/reverse-genetics and post-genomic approaches using Arabidopsis thaliana, the first higher plant to have its entire genome sequenced. These studies illustrated that plant peroxisomes have more diverse functions than we previously thought. Research using Arabidopsis thaliana is improving our understanding of the function of plant peroxisomes.
Keywords: Arabidopsis; Glyoxysome; Leaf peroxisome; Lipid metabolism; Photorespiration;
The biochemistry of oleate induction: Transcriptional upregulation and peroxisome proliferation by Aner Gurvitz; Hanspeter Rottensteiner (1392-1402).
Unicellular organisms such as yeast constantly monitor their environment and respond to nutritional cues. Rapid adaptation to ambient changes may include modification and degradation of proteins; alterations in mRNA stability; and differential rates of translation. However, for a more prolonged response, changes are initiated in the expression of genes involved in the utilization of energy sources whose availability constantly fluctuates. For example, in the presence of oleic acid as a sole carbon source, yeast cells induce the expression of a discrete set of enzymes for fatty acid β-oxidation as well as proteins involved in the expansion of the peroxisomal compartment containing this process. In this review chapter, we discuss the factors regulating oleate induction in Saccharomyces cerevisiae, and we also deal with peroxisome proliferation in other organisms, briefly mentioning fatty acid-independent signals that can trigger this process.
Keywords: Pip2p–Oaf1p; ORE, Oleate response element; Adr1p; UAS1, Upstream activation sequence type 1; Saccharomyces cerevisiae; Fatty acids;
Alpha-Oxidation by Gerbert A. Jansen; Ronald J.A. Wanders (1403-1412).
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched chain fatty acid, which is a constituent of the human diet. The presence of the 3-methyl group of phytanic acid prevents degradation by beta-oxidation. Instead, the terminal carboxyl group is first removed by alpha-oxidation. The mechanism of the alpha-oxidation pathway and the enzymes involved are described in this review.
Keywords: Alpha-oxidation; Phytanic acid; Pristanic acid; Phytol; Refsum disease; Zellweger syndrome;
Peroxisomal β-oxidation—A metabolic pathway with multiple functions by Yves Poirier; Vasily D. Antonenkov; Tuomo Glumoff; J. Kalervo Hiltunen (1413-1426).
Fatty acid degradation in most organisms occurs primarily via the β-oxidation cycle. In mammals, β-oxidation occurs in both mitochondria and peroxisomes, whereas plants and most fungi harbor the β-oxidation cycle only in the peroxisomes. Although several of the enzymes participating in this pathway in both organelles are similar, some distinct physiological roles have been uncovered. Recent advances in the structural elucidation of numerous mammalian and yeast enzymes involved in β-oxidation have shed light on the basis of the substrate specificity for several of them. Of particular interest is the structural organization and function of the type 1 and 2 multifunctional enzyme (MFE-1 and MFE-2), two enzymes evolutionarily distant yet catalyzing the same overall enzymatic reactions but via opposite stereochemistry. New data on the physiological roles of the various enzymes participating in β-oxidation have been gathered through the analysis of knockout mutants in plants, yeast and animals, as well as by the use of polyhydroxyalkanoate synthesis from β-oxidation intermediates as a tool to study carbon flux through the pathway. In plants, both forward and reverse genetics performed on the model plant Arabidopsis thaliana have revealed novel roles for β-oxidation in the germination process that is independent of the generation of carbohydrates for growth, as well as in embryo and flower development, and the generation of the phytohormone indole-3-acetic acid and the signal molecule jasmonic acid.
Keywords: β-oxidation; Metabolic compartmentalization; Fatty acid; Peroxisome; Multifunctional enzyme; Intermediary metabolism;
Peroxisomes and bile acid biosynthesis by Sacha Ferdinandusse; Sander M. Houten (1427-1440).
Peroxisomes play an important role in the biosynthesis of bile acids because a peroxisomal β-oxidation step is required for the formation of the mature C24-bile acids from C27-bile acid intermediates. In addition, de novo synthesized bile acids are conjugated within the peroxisome. In this review, we describe the current state of knowledge about all aspects of peroxisomal function in bile acid biosynthesis in health and disease. The peroxisomal enzymes involved in the synthesis of bile acids have been identified, and the metabolic and pathologic consequences of a deficiency of one of these enzymes are discussed, including the potential role of nuclear receptors therein.
Keywords: Peroxisomal β-oxidation; Nuclear receptors; C27-bile acid intermediates; Peroxisome deficiency disorders;
A central role for the peroxisomal membrane in glyoxylate cycle function by Markus Kunze; Itsara Pracharoenwattana; Steven M. Smith; Andreas Hartig (1441-1452).
The glyoxylate cycle provides the means to convert C2-units to C4-precursors for biosynthesis, allowing growth on fatty acids and C2-compounds. The conventional view that the glyoxylate cycle is contained within peroxisomes in fungi and plants is no longer valid. Glyoxylate cycle enzymes are located both inside and outside the peroxisome. Thus, the operation of the glyoxylate cycle requires transport of several intermediates across the peroxisomal membrane. Glyoxylate cycle progression is also dependent upon mitochondrial metabolism. An understanding of the operation and regulation of the glyoxylate cycle, and its integration with cellular metabolism, will require further investigation of the participating metabolite transporters in the peroxisomal membrane.
Keywords: Glyoxylate cycle; Peroxisomes; Membrane transport; Metabolic compartmentation; Saccharomyces cerevisiae; Arabidopsis thaliana;
The significance of peroxisomes in methanol metabolism in methylotrophic yeast by Ida J. van der Klei; Hiroya Yurimoto; Yasuyoshi Sakai; Marten Veenhuis (1453-1462).
The capacity to use methanol as sole source of carbon and energy is restricted to relatively few yeast species. This may be related to the low efficiency of methanol metabolism in yeast, relative to that of prokaryotes. This contribution describes the details of methanol metabolism in yeast and focuses on the significance of compartmentalization of this metabolic pathway in peroxisomes.
Keywords: Peroxisome; Yeast; Methanol metabolism;
Metabolic functions of glycosomes in trypanosomatids by Paul A.M. Michels; Frédéric Bringaud; Murielle Herman; Véronique Hannaert (1463-1477).
Protozoan Kinetoplastida, including the pathogenic trypanosomatids of the genera Trypanosoma and Leishmania, compartmentalize several important metabolic systems in their peroxisomes which are designated glycosomes. The enzymatic content of these organelles may vary considerably during the life-cycle of most trypanosomatid parasites which often are transmitted between their mammalian hosts by insects. The glycosomes of the Trypanosoma brucei form living in the mammalian bloodstream display the highest level of specialization; 90% of their protein content is made up of glycolytic enzymes. The compartmentation of glycolysis in these organelles appears essential for the regulation of this process and enables the cells to overcome short periods of anaerobiosis. Glycosomes of all other trypanosomatid forms studied contain an extended glycolytic pathway catalyzing the aerobic fermentation of glucose to succinate. In addition, these organelles contain enzymes for several other processes such as the pentose-phosphate pathway, β-oxidation of fatty acids, purine salvage, and biosynthetic pathways for pyrimidines, ether-lipids and squalenes. The enzymatic content of glycosomes is rapidly changed during differentiation of mammalian bloodstream-form trypanosomes to the forms living in the insect midgut. Autophagy appears to play an important role in trypanosomatid differentiation, and several lines of evidence indicate that it is then also involved in the degradation of old glycosomes, while a population of new organelles containing different enzymes is synthesized. The compartmentation of environment-sensitive parts of the metabolic network within glycosomes would, through this way of organelle renewal, enable the parasites to adapt rapidly and efficiently to the new conditions.
Keywords: Trypanosome; Glycosome; Glycolysis; Differentiation; Metabolic adaptation; Organelle turnover;
Plant peroxisomes as a source of signalling molecules by Yvonne Nyathi; Alison Baker (1478-1495).
Peroxisomes are pleoimorphic, metabolically plastic organelles. Their essentially oxidative function led to the adoption of the name ‘peroxisome’. The dynamic and diverse nature of peroxisome metabolism has led to the realisation that peroxisomes are an important source of signalling molecules that can function to integrate cellular activity and multicellular development. In plants defence against predators and a hostile environment is of necessity a metabolic and developmental response—a plant has no place to hide. Mutant screens are implicating peroxisomes in disease resistance and signalling in response to light. Characterisation of mutants disrupted in peroxisomal β-oxidation has led to a growing appreciation of the importance of this pathway in the production of jasmonic acid, conversion of indole butyric acid to indole acetic acid and possibly in the production of other signalling molecules. Likewise the role of peroxisomes in the production and detoxification of reactive oxygen, and possibly reactive nitrogen species and changes in redox status, suggests considerable scope for peroxisomes to contribute to perception and response to a wide range of biotic and abiotic stresses. Whereas the peroxisome is the sole site of β-oxidation in plants, the production and detoxification of ROS in many cell compartments makes the specific contribution of the peroxisome much more difficult to establish. However progress in identifying peroxisome specific isoforms of enzymes associated with ROS metabolism should allow a more definitive assessment of these contributions in the future.
Keywords: Peroxisome; β-oxidation; Hydrogen peroxide; Superoxide; Reactive oxygen specie; Nitric oxide; Stress; Defence;
Plant peroxisomes respire in the light: Some gaps of the photorespiratory C2 cycle have become filled—Others remain by Sigrun Reumann; Andreas P.M. Weber (1496-1510).
The most prominent role of peroxisomes in photosynthetic plant tissues is their participation in photorespiration, a process also known as the oxidative C2 cycle or the oxidative photosynthetic carbon cycle. Photorespiration is an essential process in land plants, as evident from the conditionally lethal phenotype of mutants deficient in enzymes or transport proteins involved in this pathway. The oxidative C2 cycle is a salvage pathway for phosphoglycolate, the product of the oxygenase activity of ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO), to the Calvin cycle intermediate phosphoglycerate. The pathway is highly compartmentalized and involves reactions in chloroplasts, peroxisomes, and mitochondria. The H2O2-producing enzyme glycolate oxidase, catalase, and several aminotransferases of the photorespiratory cycle are located in peroxisomes, with catalase representing the major constituent of the peroxisomal matrix in photosynthetic tissues. Although photorespiration is of major importance for photosynthesis, the identification of the enzymes involved in this process has only recently been completed. Only little is known about the metabolite transporters for the exchange of photorespiratory intermediates between peroxisomes and the other organelles involved, and about the regulation of the photorespiratory pathway. This review highlights recent developments in understanding photorespiration and identifies remaining gaps in our knowledge of this important metabolic pathway.
Keywords: Photorespiration; Peroxisomes; Oxidative C2 cycle; Photosynthesis; Mutant; Arabidopsis; Co-expression analysis; Bioinformatic; Pathogen defence;
The ether lipid-deficient mouse: Tracking down plasmalogen functions by Karin Gorgas; Andre Teigler; Dorde Komljenovic; Wilhelm W. Just (1511-1526).
Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their chemical structures were described and their effect on membrane fluidity and membrane fusion discussed. The recent generation of mouse models with ether lipid deficiency offered the possibility to study ether lipid and particularly plasmalogen functions in vivo. Ether lipid-deficient mice revealed severe phenotypic alterations, including arrest of spermatogenesis, development of cataract and defects in central nervous system myelination. In several cell culture systems lack of plasmalogens impaired intracellular cholesterol distribution affecting plasma membrane functions and structural changes of ER and Golgi cisternae. Based on these phenotypic anomalies that were accurately described conclusions were drawn on putative functions of plasmalogens. These functions were related to cell–cell or cell–extracellular matrix interactions, formation of lipid raft microdomains and intracellular cholesterol homeostasis. There are several human disorders, such as Zellweger syndrome, rhizomelic chondrodysplasia punctata, Alzheimer’s disease, Down syndrome, and Niemann–Pick type C disease that are distinguished by altered tissue plasmalogen concentrations. The role plasmalogens might play in the pathology of these disorders is discussed.
Keywords: Ether lipid; Plasmalogen; Sulfogalactolipid; Spermatogenesis; Lens; Neurodegenerative disease; Myelination;
The ins and outs of peroxisomes: Co-ordination of membrane transport and peroxisomal metabolism by Hanspeter Rottensteiner; Frederica L. Theodoulou (1527-1540).
Peroxisomes perform a range of metabolic functions which require the movement of substrates, co-substrates, cofactors and metabolites across the peroxisomal membrane. In this review, we discuss the evidence for and against specific transport systems involved in peroxisomal metabolism and how these operate to co-ordinate biochemical reactions within the peroxisome with those in other compartments of the cell.
Keywords: ABC transporter; β-oxidation; Adenine nucleotide translocator; Redox shuttle; Peroxisomal pH; Porin;
Proteomics of the peroxisome by R.A. Saleem; J.J. Smith; J.D. Aitchison (1541-1551).
Genomes provide us with a blue print for the potential of a cell. However, the activity of a cell is expressed in its proteome. Full understanding of the complexity of cells demands a comprehensive view of the proteome; its interactions, activity states and organization. Comprehensive proteomic approaches applied to peroxisomes have yielded new insights into the organelle and its dynamic interplay with other cellular structures. As technologies and methodologies improve, proteomics hold the promise for new discoveries of peroxisome function and a full description of this dynamic organelle.
Keywords: Peroxisome; Proteome; Mass spectrometry; Protein quantification; Protein localization; In silico prediction;
Uniqueness of the mechanism of protein import into the peroxisome matrix: Transport of folded, co-factor-bound and oligomeric proteins by shuttling receptors by Sébastien Léon; Joel M. Goodman; Suresh Subramani (1552-1564).
Based on earlier suggestions that peroxisomes may have arisen from endosymbionts that later lost their DNA, it was expected that protein transport into this organelle would have parallels to systems found in other organelles of endosymbiont origin, such as mitochondria and chloroplasts. This review highlights three features of peroxisomal matrix protein import that make it unique in comparison with these other subcellular compartments - the ability of this organelle to transport folded, co-factor-bound and oligomeric proteins, the dynamics of the import receptors during the matrix protein import cycle and the existence of a peroxisomal quality-control pathway, which insures that the peroxisome membrane is cleared of cargo-free receptors.
Keywords: Peroxisomal matrix protein import; Import of folded and oligomeric protein; Shuttling receptor; Extended shuttle; Peroxisomal RADAR; Quality-control;
Peroxisome targeting signal 1: Is it really a simple tripeptide? by Cécile Brocard; Andreas Hartig (1565-1573).
Originally, the peroxisomal targeting signal 1 (PTS1) was defined as a tripeptide at the C-terminus of proteins prone to be imported into the peroxisomal matrix. The corresponding receptor PEX5 initiates the translocation of proteins by identifying potential substrates via their C-termini and trapping PTS1s through remodeling of its TPR domain. Thorough studies on the interaction between PEX5 and PTS1 as well as sequence-analytic tools revealed the influence of amino acid residues further upstream of the ultimate tripeptide. Altogether, PTS1s should be defined as dodecamer sequences at the C-terminal ends of proteins. These sequences accommodate physical contacts with both the surface and the binding cavity of PEX5 and ensure accessibility of the extreme C-terminus. Knowledge-based approaches in applied Bioinformatics provide reliable tools to accurately predict the peroxisomal location of proteins not yet determined experimentally.
Keywords: PTS1; PEX5; Targeting; Peroxisome; Predictor;
Pex14p, more than just a docking protein by Jorge E. Azevedo; Wolfgang Schliebs (1574-1584).
After binding newly synthesized peroxisomal matrix proteins in the cytosol, the second task of Pex5p, the peroxisomal cycling receptor, is to carry these proteins to the peroxisomal membrane. Defining the nature of the events that occur at this membrane system and which ultimately result in the translocation of the cargo proteins into the matrix of the organelle and in the recycling of Pex5p back to the cytosol, is one of the major goals of the research in this field. Presently, it is generally accepted that all these steps are promoted by a large protein complex embedded in the peroxisomal membrane. This docking/translocation machinery or importomer, as it is often called, comprises many different peroxins of which one of the best characterized is Pex14p. Here, we review data regarding this membrane peroxin with emphasis on the interactions that it establishes with Pex5p. The available evidence suggests that the key to understand how folded proteins are capable of passing an apparently impermeable membrane may largely reside in this pair of peroxins.
Keywords: Peroxisome; Protein import; PTS1-receptor; Pex5p; Pex14p; Importomer;
Pex13p: Docking or cargo handling protein? by Chris Williams; Ben Distel (1585-1591).
The Src homology 3 (SH3) domain-containing peroxisomal membrane protein Pex13p is an essential component of the import machinery for matrix proteins and forms a binding site for the peroxisomal targeting type I (PTS1) receptor Pex5p. The interaction between these two proteins can be described as novel in several ways. In the yeasts Saccharomyces cerevisiae and Pichia pastoris, the SH3 domain itself is responsible for the interaction but not via the typical P-x-x-P motifs that are common to SH3 ligands as Pex5p lacks such a motif. Instead, a region of Pex5p containing a W-x-x-x-F/Y motif is crucial for this binding. In mammals, again W-x-x-x-F/Y motifs appear to be important for the interaction but the SH3 domain seems not to be the site for Pex5p binding, this being located in the N-terminus of Pex13p. Despite these differences in the details of the Pex13p–Pex5p interaction, the association of the two proteins is a crucial step in Pex5p-mediated protein import into peroxisomes in both yeasts and mammals.
Keywords: Pex5p; Pex13p; SH3 domain; P-x-x-P motif; Peroxisome; W-x-x-x-F/Y motif; Protein import;
Dynamic architecture of the peroxisomal import receptor Pex5p by Will A. Stanley; Matthias Wilmanns (1592-1598).
The majority of peroxisomal matrix proteins are recognized by the import receptor Pex5p. The receptor is dynamic in terms of its overall architecture and association with the peroxisomal membrane. It participates in different protein complexes during the translocation of cargos from the cytosol to the peroxisomal matrix. Its sequence comprises two structurally and functionally autonomous parts. The N-terminal segment interacts with several peroxins that assemble into distinct protein complexes during cargo translocation. Despite evidence for α-helical binding motifs for some of these components (Pex13p, Pex14p) its overall appearance is that of a molten globule and folding/unfolding transitions may play a critical role in its function. In contrast, most of the C-terminal part of the receptor folds into a ring-like α-helical structure and binds folded and functionally intact peroxisomal targets that bear a C-terminal peroxisomal targeting signal type-1. Some of these targets also bind to secondary binding sites of the receptor.
Keywords: Receptor; Structure; Cargo import; Peroxisomal targeting signal; Translocon;
Chapter 3.1.7. The import receptor Pex7p and the PTS2 targeting sequence by Paul B. Lazarow (1599-1604).
This chapter concerns one branch of the peroxisome import pathway for newly-synthesized peroxisomal proteins, specifically the branch for matrix proteins that contain a peroxisome targeting sequence type 2 (PTS2). The structure and utilization of the PTS2 are discussed, as well as the properties of the receptor, Pex7p, which recognizes the PTS2 sequence and conveys these proteins to the common translocation machinery in the peroxisome membrane. We also describe the recent evidence that this receptor recycles into the peroxisome matrix and back out to the cytosol in the course of its function. Pex7p is assisted in its functioning by several species-specific auxiliary proteins that are described in the following chapter.
Keywords: Peroxisome targeting sequence; PTS2; Pex7p; Receptor;
PTS2 Co-receptors: Diverse proteins with common features by Wolfgang Schliebs; Wolf-H. Kunau (1605-1612).
One feature of the PTS2 import pathway is the separation of the roles of the PTS receptor between two proteins. Pex7p alone is insufficient to act as the receptor for the import cycle for peroxisomal matrix proteins. In all cases, Pex7p needs a PTS2 co-receptor to form an import-competent PTS2 receptor complex together with the PTS2 cargo. We provide an overview of the proteins that have been identified as PTS2 co-receptors and discuss their proposed functions.
Keywords: Peroxisome; Protein import; PTS2-receptor; Pex5p; Co-receptor;
The importomer—A peroxisomal membrane complex involved in protein translocation into the peroxisome matrix by Naganand Rayapuram; Suresh Subramani (1613-1619).
The import of proteins into the peroxisome matrix is an essential step in peroxisome biogenesis, which is critical for normal functioning of most eukaryotic cells. The translocation of proteins across the peroxisome membrane and the dynamic behavior of the import receptors during the import cycle is facilitated by several peroxisome–membrane-associated protein complexes, one of which is called the importomer complex [B. Agne, N.M. Meindl, K. Niederhoff, H. Einwachter, P. Rehling, A. Sickmann, H.E. Meyer, W. Girzalsky, W.H. Kunau, Pex8p: an intraperoxisomal organizer of the peroxisomal import machinery, Mol. Cell 11 (2003) 635–646; P.P. Hazra, I. Suriapranata, W.B. Snyder, S. Subramani, Peroxisome remnants in pex3Δ cells and the requirement of Pex3p for interactions between the peroxisomal docking and translocation subcomplexes, Traffic 3 (2002) 560–574. ]. We provide below a brief historical perspective regarding the importomer and its role in peroxisome biogenesis. We also identify areas in which further work is needed to uncover the physiological role of the importomer.
Keywords: Importomer; Docking and RING subcomplexes; Peroxisomal matrix protein import;
Peroxisomal matrix protein receptor ubiquitination and recycling by Sven Thoms; Ralf Erdmann (1620-1628).
The peroxisomal targeting signal type1 (PTS1) receptor Pex5 is required for the peroxisomal targeting of most matrix proteins. Pex5 recognises target proteins in the cytosol and directs them to the peroxisomal membrane where cargo is released into the matrix, and the receptor shuttles back to the cytosol. Recently, it has become evident that the membrane-bound Pex5 can be modified by mono- and polyubiquitination. This review summarises recent results on Pex5 ubiquitination and on the role of the AAA peroxins Pex1 and Pex6 as dislocases required for the release of Pex5 from the membrane to the cytosol where the receptor is either degraded by proteasomes or made available for another round of protein import into peroxisomes.
Keywords: AAA protein; Peroxisome biogenesis; Pex1p; Pex6p; Pex5p; Pex15p; Peroxin; Ubiquitin;
Targeting signals in peroxisomal membrane proteins by Elke Van Ael; Marc Fransen (1629-1638).
Peroxisomal membrane proteins (PMPs) are encoded by the nuclear genome and translated on cytoplasmic ribosomes. Newly synthesized PMPs can be targeted directly from the cytoplasm to peroxisomes or travel to peroxisomes via the endoplasmic reticulum (ER). The mechanisms responsible for the targeting of these proteins to the peroxisomal membrane are still rather poorly understood. However, it is clear that the trafficking of PMPs to peroxisomes depends on the presence of cis-acting targeting signals, called mPTSs. These mPTSs show great variability both in the identity and number of requisite residues. An emerging view is that mPTSs consist of at least two functionally distinct domains: a targeting element, which directs the newly synthesized PMP from the cytoplasm to its target membrane, and a membrane-anchoring sequence, which is required for the permanent insertion of the protein into the peroxisomal membrane. In this review, we summarize our knowledge of the mPTSs currently identified.
Keywords: Peroxisome; Membrane protein; Protein import; mPTS; Pex19p; Peroxin;
Import of peroxisomal membrane proteins: The interplay of Pex3p- and Pex19p-mediated interactions by Yukio Fujiki; Yuji Matsuzono; Takashi Matsuzaki; Marc Fransen (1639-1646).
In contrast to the molecular mechanisms underlying import of peroxisomal matrix proteins, those involving the transport of membrane proteins remain rather elusive. At present, two targeting routes for peroxisomal membrane proteins (PMPs) have been depicted: class I PMPs are targeted from the cytoplasm directly to the peroxisome membrane, and class II PMPs are sorted indirectly to peroxisomes via the endoplasmic reticulum (ER). In addition, three peroxins – Pex3p, Pex16p, and Pex19p – have been identified as essential factors for PMP assembly in several species including humans: Pex19p is a predominantly cytoplasmic protein that shows a broad PMP-binding specificity; Pex3p serves as the membrane-anchoring site for Pex19p; and Pex16p – a protein absent in most yeasts – is thought to provide the initial scaffold for recruiting the protein import machinery required for peroxisome membrane biogenesis. Remarkably, the function of Pex16p does not appear to be conserved between different species. In addition, significant disagreement exists about whether Pex19p has a chaperone-like role in the cytosol or at the peroxisome membrane and/or functions as a cycling import receptor for newly synthesized PMPs. Here we review the recent progress made in our understanding of the role of two key players in PMP biogenesis, Pex3p and Pex19p.
Keywords: Membrane biogenesis; Peroxin; Chaperone; Membrane protein transporter; Protein import; Zellweger syndrome;
Formation of peroxisomes: Present and past by H.F. Tabak; D. Hoepfner; A. v.d. Zand; H.J. Geuze; I. Braakman; M.A. Huynen (1647-1654).
Eukaryotic cells contain functionally distinct, membrane enclosed compartments called organelles. Here we like to address two questions concerning this architectural lay out. How did this membrane complexity arise during evolution and how is this collection of organelles maintained in multiplying cells to ensure that new cells retain a complete set of them. We will try to address these questions with peroxisomes as a focal point of interest.
Keywords: Peroxisome; Evolution; Endoplasmic reticulum;
The ER-peroxisome connection in plants: Development of the “ER semi-autonomous peroxisome maturation and replication” model for plant peroxisome biogenesis by Robert T. Mullen; Richard N. Trelease (1655-1668).
The perceived role of the ER in the biogenesis of plant peroxisomes has evolved significantly from the original “ER vesiculation” model, which portrayed co-translational import of proteins into peroxisomes originating from the ER, to the “ER semi-autonomous peroxisome” model wherein membrane lipids and post-translationally acquired peroxisomal membrane proteins (PMPs) were derived from the ER. Results from more recent studies of various plant PMPs including ascorbate peroxidase, PEX10 and PEX16, as well as a viral replication protein, have since led to the formulation of a more elaborate “ER semi-autonomous peroxisome maturation and replication” model. Herein we review these results in the context of this newly proposed model and its predecessor models. We discuss also key distinct features of the new model pertaining to its central premise that the ER defines the semi-autonomous maturation (maintenance/assembly/differentiation) and duplication (division) features of specialized classes of pre-existing plant peroxisomes. This model also includes a novel peroxisome-to-ER retrograde sorting pathway that may serve as a constitutive protein retrieval/regulatory system. In addition, new plant peroxisomes are envisaged to arise primarily by duplication of the pre-existing peroxisomes that receive essential membrane components from the ER.
Keywords: Biogenesis; Endoplasmic reticulum; Peroxisome; Plant; Protein trafficking; Organelle;
Sharing the wealth: Peroxisome inheritance in budding yeast by Monica Fagarasanu; Andrei Fagarasanu; Richard A. Rachubinski (1669-1677).
Eukaryotic cells have evolved molecular mechanisms to ensure the faithful partitioning of cellular components during cell division. The budding yeast Saccharomyces cerevisiae has to actively deliver about half of its organelles to the growing bud, while retaining the remaining organelles in the mother cell. Until lately, little was known about the inheritance of peroxisomes. Recent studies have identified the peroxisomal proteins Inp1p and Inp2p as two key regulators of peroxisome inheritance that perform antagonistic functions. Inp1p is required for the retention of peroxisomes in mother cells, whereas Inp2p promotes the bud-directed movement of these organelles. Inp1p anchors peroxisomes to the cell cortex by interacting with specific structures lining the cell periphery. On the other hand, Inp2p functions as the peroxisome-specific receptor for the class V myosin, Myo2p, thereby linking peroxisomes to the translocation machinery that propels peroxisome movement. Tight coordination between Inp1p and Inp2p ensures a fair and harmonious spatial segregation of peroxisomes upon cell division.
Keywords: Peroxisome; Inheritance; Budding yeast; Inp1p; Inp2p; Myo2p;
Peroxisome biogenesis: Where Arf and coatomer might be involved by Dorothee Lay; Karin Gorgas; Wilhelm W. Just (1678-1687).
The present review summarizes recent observations on binding of Arf and COPI coat to isolated rat liver peroxisomes. The general structural and functional features of both Arf and coatomer were considered along with the requirements and dependencies of peroxisomal Arf and coatomer recruitment. Studies on the expression of mammalian Pex11 proteins, mainly Pex11α and Pex11β, intimately related to the process of peroxisome proliferation, revealed a sequence of individual steps including organelle elongation/tubulation, formation of membrane and matrix protein patches segregating distinct proteins from each other, development of membrane constrictions and final membrane fission. Based on the similarities of the processes leading to cargo selection and concentration on Golgi membranes on the one hand and to the formation of peroxisomal protein patches on the other hand, an implication of Arf and COPI in distinct processes of peroxisomal proliferation is hypothesized. Alternatively, peroxisomal Arf/COPI might facilitate the formation of COPI-coated peroxisomal vesicles functioning in cargo transport and retrieval from peroxisomes to the ER. Recent observations suggesting transport of Pex3 and Pex19 during early steps of peroxisome biogenesis from the ER to peroxisomes inevitably propose such a retrieval mechanism, provided the ER to peroxisome pathway is based on transporting vesicles.
Keywords: Peroxisome; Biogenesis; Arf; Small GTPase; Coatomer; COPI;
Lipids and lipid domains in the peroxisomal membrane of the yeast Yarrowia lipolytica by Tatiana Boukh-Viner; Vladimir I. Titorenko (1688-1696).
Biological membranes have unique and highly diverse compositions of their lipid constituents. At present, we have only partial understanding of how membrane lipids and lipid domains regulate the structural integrity and functionality of cellular organelles, maintain the unique molecular composition of each organellar membrane by orchestrating the intracellular trafficking of membrane-bound proteins and lipids, and control the steady-state levels of numerous signaling molecules generated in biological membranes. Similar to other organellar membranes, a single lipid bilayer enclosing the peroxisome, an organelle known for its essential role in lipid metabolism, has a unique lipid composition and organizes some of its lipid and protein components into distinctive assemblies. This review highlights recent advances in our knowledge of how lipids and lipid domains of the peroxisomal membrane regulate the processes of peroxisome assembly and maintenance in the yeast Yarrowia lipolytica. We critically evaluate the molecular mechanisms through which lipid constituents of the peroxisomal membrane control these multistep processes and outline directions for future research in this field.
Keywords: Organelle biogenesis; Membrane structure; Membrane domain; Membrane lipid; Lipid raft; Peroxisome assembly;
Peroxisomal membrane permeability and solute transfer by Vasily D. Antonenkov; J. Kalervo Hiltunen (1697-1706).
The review is dedicated to recent progress in the study of peroxisomal membrane permeability to solutes which has been a matter of debate for more than 40 years. Apparently, the mammalian peroxisomal membrane is freely permeable to small solute molecules owing to the presence of pore-forming channels. However, the membrane forms a permeability barrier for ‘bulky’ solutes including cofactors (NAD/H, NADP/H, CoA, and acetyl/acyl-CoA esters) and ATP. Therefore, peroxisomes need specific protein transporters to transfer these compounds across the membrane. Recent electrophysiological studies have revealed channel-forming activities in the mammalian peroxisomal membrane. The possible involvement of the channels in the transfer of small metabolites and in the formation of peroxisomal shuttle systems is described.
Keywords: Peroxisome; Membrane permeability; Channel; Transporter;
Peroxisomal disorders: The single peroxisomal enzyme deficiencies by Ronald J.A. Wanders; Hans R. Waterham (1707-1720).
Peroxisomal disorders are a group of inherited diseases in man in which either peroxisome biogenesis or one or more peroxisomal functions are impaired. The peroxisomal disorders identified to date are usually classified in two groups including: (1) the disorders of peroxisome biogenesis, and (2) the single peroxisomal enzyme deficiencies. This review is focused on the second group of disorders, which currently includes ten different diseases in which the mutant gene affects a protein involved in one of the following peroxisomal functions: (1) ether phospholipid (plasmalogen) biosynthesis; (2) fatty acid beta-oxidation; (3) peroxisomal alpha-oxidation; (4) glyoxylate detoxification, and (5) H2O2 metabolism.
Keywords: Peroxisomes; Alpha-oxidation; Beta-oxidation; Zellweger syndrome; Refsum disease; Adrenoleukodystrophy; Hyperoxaluria; Plasmalogen;
X-linked adrenoleukodystrophy: Clinical, biochemical and pathogenetic aspects by Johannes Berger; Jutta Gärtner (1721-1732).
X-linked adrenoleukodystrophy (X-ALD) is a clinically heterogeneous disorder ranging from the severe childhood cerebral form to asymptomatic persons. The overall incidence is 1:16,800 including hemizygotes as well as heterozygotes. The principal molecular defect is due to inborn mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP), a transporter in the peroxisome membrane. ALDP is involved in the transport of substrates from the cytoplasm into the peroxisomal lumen. ALDP defects lead to characteristic accumulation of saturated very long-chain fatty acids, the diagnostic disease marker. The pathogenesis is unclear. Different molecular mechanisms seem to induce inflammatory demyelination, neurodegeneration and adrenocortical insufficiency involving the primary ABCD1 defect, environmental factors and modifier genes. Important information has been derived from the X-ALD mouse models; species differences however complicate the interpretation of results. So far, bone marrow transplantation is the only effective long-term treatment for childhood cerebral X-ALD, however, only when performed at an early-stage of disease. Urgently needed novel therapeutic strategies are under consideration ranging from dietary approaches to gene therapy.
Keywords: Adrenoleukodystrophy; Peroxisome; ABC-transporter; Leukodystrophy; Neurodegeneration; Mouse model;
Peroxisome biogenesis disorders by Steven J. Steinberg; Gabriele Dodt; Gerald V. Raymond; Nancy E. Braverman; Ann B. Moser; Hugo W. Moser (1733-1748).
Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). PBD are divided into two types—Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata (RCDP). Biochemical studies performed in blood and urine are used to screen for the PBD. DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD. In contrast, PBD-RCDP is associated with defects in the PEX7 gene alone. Studies of the cellular and molecular defects in PBD patients have contributed significantly to our understanding of the role of each PEX gene in peroxisome assembly.
Keywords: Zellweger syndrome; Neonatal adrenoleukodystrophy; Infantile refsum disease; Rhizomelic chondrodysplasia punctata; PEX;
Peroxisomes and aging by Stanley R. Terlecky; Jay I. Koepke; Paul A. Walton (1749-1754).
Peroxisomes are indispensable for proper functioning of human cells. They efficiently compartmentalize enzymes responsible for a number of metabolic processes, including the absolutely essential β-oxidation of specific fatty acid chains. These and other oxidative reactions produce hydrogen peroxide, which is, in most instances, immediately processed in situ to water and oxygen. The responsible peroxidase is the heme-containing tetrameric enzyme, catalase. What has emerged in recent years is that there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset—leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific xenobiotics. The overall goal of this review is to summarize the molecular events associated with the development and advancement of peroxisomal hypocatalasemia and to describe its effects on cells. In addition, results of recent efforts to increase levels of peroxisomal catalase and restore oxidative balance in cells will be discussed.
Keywords: Aging; Catalase; Peroxisome; Protein import; Reactive oxygen specie; Senescence;
Peroxisomes and oxidative stress by Michael Schrader; H.Dariush Fahimi (1755-1766).
The discovery of the colocalization of catalase with H2O2-generating oxidases in peroxisomes was the first indication of their involvement in the metabolism of oxygen metabolites. In past decades it has been revealed that peroxisomes participate not only in the generation of reactive oxygen species (ROS) with grave consequences for cell fate such as malignant degeneration but also in cell rescue from the damaging effects of such radicals. In this review the role of peroxisomes in a variety of physiological and pathological processes involving ROS mainly in animal cells is presented. At the outset the enzymes generating and scavenging H2O2 and other oxygen metabolites are reviewed. The exposure of cultured cells to UV light and different oxidizing agents induces peroxisome proliferation with formation of tubular peroxisomes and apparent upregulation of PEX genes. Significant reduction of peroxisomal volume density and several of their enzymes is observed in inflammatory processes such as infections, ischemia–reperfusion injury and hepatic allograft rejection. The latter response is related to the suppressive effects of TNFα on peroxisomal function and on PPARα. Their massive proliferation induced by a variety of xenobiotics and the subsequent tumor formation in rodents is evidently due to an imbalance in the formation and scavenging of ROS, and is mediated by PPARα. In PEX5−/− mice with the absence of functional peroxisomes severe abnormalities of mitochondria in different organs are observed which resemble closely those in respiratory chain disorders associated with oxidative stress. Interestingly, no evidence of oxidative damage to proteins or lipids, nor of increased peroxide production has been found in that mouse model. In this respect the role of PPARα, which is highly activated in those mice, in prevention of oxidative stress deserves further investigation.
Keywords: ROS; Peroxisome proliferation; Oxygen; Antioxidant enzymes; PEX5−/− mice; Oxidative injury;
Pexophagy: Autophagic degradation of peroxisomes by Yasuyoshi Sakai; Masahide Oku; Ida J. van der Klei; Jan A.K.W. Kiel (1767-1775).
The abundance of peroxisomes within a cell can rapidly decrease by selective autophagic degradation (also designated pexophagy). Studies in yeast species have shown that at least two modes of peroxisome degradation are employed, namely macropexophagy and micropexophagy. During macropexophagy, peroxisomes are individually sequestered by membranes, thus forming a pexophagosome. This structure fuses with the vacuolar membrane, resulting in exposure of the incorporated peroxisome to vacuolar hydrolases. During micropexophagy, a cluster of peroxisomes is enclosed by vacuolar membrane protrusions and/or segmented vacuoles as well as a newly formed membrane structure, the micropexophagy-specific membrane apparatus (MIPA), which mediates the enclosement of the vacuolar membrane. Subsequently, the engulfed peroxisome cluster is degraded. This review discusses the current state of knowledge of pexophagy with emphasis on studies on methylotrophic yeast species.
Keywords: ATG gene; Autophagy; Peroxin; Pexophagy; Sequestration; Vacuole;
Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways by Christopher J. Danpure (1776-1784).
Primary hyperoxaluria type 1 (PH1) is an atypical peroxisomal disorder, as befits a deficiency of alanine:glyoxylate aminotransferase (AGT), which is itself an atypical peroxisomal enzyme. PH1 is characterized by excessive synthesis and excretion of the metabolic end-product oxalate and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract. Disease in many patients is caused by a unique protein trafficking defect in which AGT is mistargeted from peroxisomes to mitochondria, where it is metabolically ineffectual, despite remaining catalytically active. Although the peroxisomal import of human AGT is dependent upon the PTS1 import receptor PEX5p, its PTS1 is exquisitely specific for mammalian AGT, suggesting the presence of additional peroxisomal targeting information elsewhere in the AGT molecule. This and many other functional peculiarities of AGT are probably a consequence of its rather chequered evolutionary history, during which much of its time has been spent being a mitochondrial, rather than a peroxisomal, enzyme. Analysis of the molecular basis of AGT mistargeting in PH1 has thrown into sharp relief some of the fundamental differences between the requirements of the peroxisomal and mitochondrial protein import pathways, particularly the properties of peroxisomal and mitochondrial matrix targeting sequences and the different conformational limitations placed upon importable cargos.
Keywords: Alanine:glyoxylate aminotransferase; Kidney stone; Mitochondrial protein trafficking; Oxalate metabolism; Peroxisomal protein trafficking; Primary hyperoxaluria type 1;
Generalised and conditional inactivation of Pex genes in mice by Myriam Baes; Paul P. Van Veldhoven (1785-1793).
During the past 10 years, several Pex genes have been knocked out in the mouse with the purpose to generate models to study the pathogenesis of peroxisome biogenesis disorders and/or to investigate the physiological importance of the Pex proteins. More recently, mice with selective inactivation of a Pex gene in particular cell types were created. The metabolic abnormalities in peroxisome deficient mice paralleled to a large extent those of Zellweger patients. Several but not all of the clinical and histological features reported in patients also occurred in peroxisome deficient mice as for example hypotonia, cortical and cerebellar malformations, endochondral ossification defects, hepatomegaly, liver fibrosis and ultrastructural abnormalities of mitochondria in hepatocytes. Although the molecular origins of the observed pathologies have not yet been resolved, several new insights on the importance of peroxisomes in different tissues have emerged.
Keywords: Pex gene; Peroxisome; Knockout; Mouse model; Zellweger syndrome; Conditional gene inactivation;
PTS1-independent sorting of peroxisomal matrix proteins by Pex5p by Ida J. van der Klei; Marten Veenhuis (1794-1800).
Most peroxisomal matrix proteins contain a peroxisomal targeting signal 1 (PTS1) for sorting to the correct organelle. This signal is located at the extreme C-terminus and generally consists of only three amino acids. The PTS1 is recognized by the receptor protein Pex5p. Several examples have been reported of peroxisomal matrix proteins that are sorted to peroxisomes via Pex5p, but lack a typical PTS1 tripeptide. In this contribution we present an overview of these so-called non-PTS1 proteins and discuss the current knowledge of the molecular mechanisms involved in their sorting.
Keywords: Peroxisome; Pex5p; PTS1; PTS2; Acyl CoA oxidase; Alcohol oxidase;
Molecular Cell Research Cumulative Contents (1801-1808).