REVIEW ARTICLE Dynamin-related proteins and Pex11 proteins in peroxisome division and proliferation Sven Thoms and Ralf Erdmann Ruhr-University-Bochum, Medical Faculty, Institute of Physiological Chemistry, Bochum, Germany Keywords dynamin-related protein; dynamin; endoplasmic reticulum; GTPase; organelle division; peroxisome proliferator-activated receptor; peroxisome; PEX11; VPS1; yeast Correspondence R Erdmann, Systems Biochemistry, Institute of Physiological Chemistry, Ruhr-University-Bochum, 44780 Bochum, Germany Fax: +49 234321 4266 Tel: +49 234322 4943 E-mail: ralf.erdmann@rub.de The abundance and size of cellular organelles vary depending on the cell type and metabolic needs Peroxisomes constitute a class of cellular organelles renowned for their ability to adapt to cellular and environmental conditions Together with transcriptional regulators, two groups of peroxisomal proteins have a pronounced influence on peroxisome size and abundance Pex11-type peroxisome proliferators are involved in the proliferation of peroxisomes, defined here as an increase in size and ⁄ or number of peroxisomes Dynamin-related proteins have recently been suggested to be required for the scission of peroxisomal membranes This review surveys the function of Pex11-type peroxisome proliferators and dynamin-related proteins in peroxisomal proliferation and division (Received 28 July 2005, accepted 26 August 2005) doi:10.1111/j.1742-4658.2005.04939.x Introduction Peroxisomes (or microbodies) are single-membrane bound organelles comprising plant glyoxisomes, kinetoplastid glycosomes, Woronin bodies and peroxisomes in the narrow sense Peroxisomes are very diverse in their metabolic functions Depending on species, cell type, and environmental conditions, peroxisomes may perform different metabolic activities, including fatty acid a- and b-oxidation, alcohol oxidation, ether-lipid biosynthesis, glycolysis, and glycerol metabolism [1] In contrast to their metabolic heterogeneity, the biogenesis of peroxisomes seems to follow a common pathway, relying on conserved proteins, the so-called peroxins Most peroxins are involved in matrix protein import or in formation of the peroxisomal membrane [2] A surprisingly large number of peroxins, however, is required for the proliferation and inheritance of these organelles The relevance of peroxisomes for human health is underscored by the existence of peroxisomal biogenesis disorders (PBDs) [3,4] These diseases are characterized by defects in peroxisome protein import, which leads to an impairment of all peroxisomal functions, with the accumulation of a- and b-oxidation substrates (such as very long chain fatty acids or phytanic acid) and a reduction in plasmalogen levels PBDs are associated with a number of more pleiotropic abnormalities, such as hypotonia, developmental delay, defects in neuronal migration and apoptosis, and hepatic and renal problems At the cellular level, mitochondria can also be affected in PBDs, probably because of their metabolic interrelation with peroxisomes [5–7] Abbreviations DRP, dynamin-related protein; GED, GTPase effector domain; PBD, peroxisomal biogenesis disorder; PCD, programmed cell death; PPAR, peroxisome proliferator-activated receptor alpha; PPP, Pex11-type peroxisome proliferators; PPRE, peroxisome proliferator-responsive elements; PRD, proline- and arginine-rich domain FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS 5169 Peroxisome proliferation The abundance of peroxisomes in a cell is regulated by a number of as yet incompletely understood processes These can – at least conceptually – be divided into (a) peroxisome proliferation by division, (b) peroxisome de novo biogenesis, (c) peroxisome inheritance, and (d) peroxisome degradation by pexophagy, an autophagy-related process Our knowledge about the relative contributions of these processes to maintain or establish a certain number of peroxisomes in a cell, is rather limited However, at least two classes of proteins are involved in controlling peroxisome number and division This review offers an overview of these two classes, namely dynamin-related proteins (DRPs) [8], and Pex11-type peroxisome proliferators (PPPs) Proliferation is understood here as a process that leads to an increase in size and ⁄ or number of peroxisomes Peroxisome proliferation at large The idea of peroxisome biogenesis by ‘growth and division’ was put forward in a very influential review 20 years ago [9] Based on the post-translational import of matrix proteins and one major membrane protein [10,11], it has become a largely accepted dogma that membrane proteins, as well as matrix proteins, are imported post-translationally from the cytosol In the light of recent research, however, a substantial contribution from the endoplasmic reticulum seems likely [12–16] In yeast, fatty acids cause the proliferation of peroxisomes [17] and the transcriptional up-regulation of peroxisomal b-oxidation enzymes This response is mediated by the oleate response element, together with the transcription factor complex, Pip2–Oaf1 [18–20], and the transcription factor, Adr1 [21,22] Adr1 regulates expression of the peroxisome-specific acyl-CoA oxidase FOX1 ⁄ POX1 as well as of PEX11 [23] Early work on peroxisome division in Candida boidinii has shown that small peroxisomes carrying an incomplete set of matrix proteins divide and mature by protein import only after a large number of immature peroxisomes have been formed [24] This work was extended by a comparative study using different growth conditions to induce peroxisomes [25] It was found that certain peroxisome-inducing conditions, such as d-alanine, methanol or oleate, up-regulate peroxisome-resident enzymes in a specific manner, rather than causing a general increase in peroxisome number These findings underscore the variability and versatility of these organelles Five different immature peroxisome populations have been identified in the yeast Yarrowia lipolytica, 5170 S Thoms and R Erdmann which are described to mature by movement through an ordered pathway [26] In the course of peroxisome maturation, acyl-CoA oxidase moves in a heteropentameric complex from the matrix to the inner membrane of the peroxisome The membrane-bound pool of acylCoA oxidase interacts with Pex16, which is also membrane bound inside the peroxisome The substrate– Pex16 interaction inhibits the negative influence of Pex16 on peroxisome division and thereby allows peroxisome division [27] ‘Growth and division’ not follow the same course in all species In Y lipolytica, and similarly in Hansenula polymorpha, peroxisomal vesicles not divide before they have matured after the import of matrix proteins [28,29] In contrast, in C boidinii, immature peroxisomes that have only acquired part of their matrix protein content seem prone to divide [30] In human cells, however, both mature and immature peroxisomes have the capability to divide [31] Whether these differences truly reflect species differences, or if they are a result of different methods, remains to be evaluated In mammalian cells, peroxisome proliferator-activated receptor alpha (PPARa) is critical for peroxisome induction [32] PPARa belongs to the superfamily of ligand-activated nuclear transcription factors [33–36] The ligands of these receptors are lipids, lipophilic substances, together with synthetic hypolipidaemic drugs, or peroxisome proliferators PPARs bind to peroxisome proliferator-responsive elements (PPREs) in a heterodimer with retinoid X receptor PPARa is expressed in adipose tissue and liver Its target gene products are involved in lipid catabolism such as fatty acid uptake, storage and oxidation (in peroxisomes and mitochondria), and in lipoprotein assembly and transport Two other PPAR subtypes have been described: PPARb (¼ PPARd) and PPARc PPARb is ubiquitously expressed, and PPARc is expressed mainly in adipose tissue, but also in colon, the immune system, and in the retina PPARc controls the differentiation of adipose tissue and fatty acid storage and mobilization In spite of their name, PPARb and PPARc have not been associated with peroxisome proliferation PPARs are involved in diseases such as diabetes, obesity, atherosclerosis, and cancer, which explains the high interest in pharmacological control of these proteins A clear-cut evaluation of PPAR effects, however, is hampered by species differences between rodents and humans, which might, in part, be explained by different expression levels [37] resulting from differences in the PPREs [38], leading to nonconserved responses to peroxisome proliferators FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS S Thoms and R Erdmann Pex11 proteins in peroxisome proliferation Pex11 was the first protein identified as being involved in peroxisome proliferation or division in yeast [39,40] Loss of PEX11 leads to reduced peroxisome abundance with giant peroxisomes [39] Similarly, depletion of Trypanosoma brucei PEX11 (TbPex11) reduces glycosome number and size [41] Conversely, overexpression of PEX11 promotes peroxisome elongation and proliferation in yeast [40], and TbPex11 overexpression causes elongation and clustering of glycosomes [41] Pex11-mediated peroxisome division is described as a process consisting of up to four partially overlapping steps [42], namely (a) the insertion of Pex11 into the membrane, (b) the elongation of peroxisomes, (c) the segregation of Pex11 and the formation of Pex11enriched patches, and (d) the division of peroxisomes (Fig 1) In all organisms studied to date, microbody abundance can be increased by the expression of extra copies of PEX11 Recently, this was confirmed for Penicillium chrysogenum, where PEX11 overexpression likewise leads to the proliferation of microbodies and an increase in penicillin production, which is not accompanied by a significant increase in penicillin biosynthesis enzymes [43] PEX11-induced penicillin overproduction in P chrysogenum could be explained by increased metabolite transport through the microbody membrane and might prove commercially relevant Pex11 function has mostly been analysed in Saccharomyces cerevisiae, trypanosoma, and mammals Diverse as the peroxisome functions are in these organisms, a requirement of the three Pex11 isoforms seems to be a common factor Fig Model of peroxisome proliferation and division (1) Elongation (2) Segregation (3) Constriction (4) Fission ⁄ division For details see the text FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS Peroxisome proliferation Three Pex11 isoforms in mammals In mammals, three isoforms of Pex11 – Pex11a, Pex11b, and Pex11c – have been identified [42,44,45] All three isoforms are described as membrane proteins with two transmembrane domains and both termini exposed to the cytosol PEX11a is inducible by inducers of peroxisome proliferation Its expression is highest in liver, kidney, heart, and testis [42,45–47] A PEX11a knockout mouse is morphologically indistinguishable from a wild-type mouse, with no obvious effect on peroxisome number or metabolism [47], suggesting that its loss can be largely compensated by other Pex11 isoforms The induction of peroxisome proliferation through PPARa by ciprofibrate does not require PEX11a, but leads to the clustering of mitochondria around lipid droplets and abnormally straight mitochondrial cristae [47] In contrast, the nonclassical peroxisome proliferator, phenylbutyrate, works independently of PPARa, but is PEX11-dependent [47] Phenylbutyrate also induces the adrenoleucodystophy-related gene (ALDP) [48] The second isoform of Pex11, Pex11b, is not inducible by peroxisome proliferators It is constitutively expressed in most tissues [44] Overexpression of PEX11b induces peroxisome proliferation to a greater extent than overexpression of PEX11a [42] The knockout of PEX11b in mice leads to neonatal lethality with a number of defects reminiscent of Zellweger, including developmental delay, hypotonia, neuronal migration defects, and neuronal apoptosis [49] These mice are, however, only mildly affected in peroxisome protein import and metabolism (reduced ether lipid biosynthesis) [49] This prompts the idea that some of the pathological features of Zellweger are not caused by gross metabolic disturbances but rather by subtle effects on signalling pathways involving peroxisomal substrates or products In cases where only a limited number of metabolites would have to be normalized, this could raise hope for therapeutic intervention in peroxisomal diseases Knockout mice with deletion of both PEX11a and PEX11b still contain peroxisomes and are only mildly affected in peroxisomal metabolic activity [49] These mice also die early after birth with severe neurological defects [49] In summary, PEX11a seems to be responsible for peroxisome proliferation in response to external stimuli, whereas PEX11b is required for constitutive peroxisome biogenesis The third isoform, Pex11c, is constitutively expressed in liver [50] and might have a redundant function with Pex11b, although it is with 22% amino 5171 Peroxisome proliferation acid identity less similar to Pex11b than Pex11a is to Pex11b (40% amino acid identity) New members of the PEX11 family in yeast Recently, proteins with a weak similarity to Pex11 have been identified in S cerevisiae [51–53] The new Pex11 proteins, Pex25 and Pex27, are more similar to each other (18% identity) than to Pex11 ( 9% identity) Pex25 (45 kDa) and Pex27 (44 kDa) have a higher molecular mass than Pex11 (27 kDa); in fact, they appear to have an N-terminal extension when compared with Pex11 All three proteins localize to peroxisomes Pex25 behaves as a peripheral membrane protein [51] The knockout of PEX25 has a stronger growth defect on oleic acid than the deletion of PEX27 The double knockout of PEX25 and PEX27 has about the same growth defect on oleic acid as the PEX25 single knockout [51,52] Growth of this double deletion can be restored by low copy expression of PEX25 or high copy expression of PEX27 [51] The triple deletion of all three PPPs is unable to grow on oleic acid [51], indicating that at least one of the Pex11 proteins is required for peroxisome biogenesis The growth defect of the triple mutant can be alleviated by the overexpression of PEX25, but not by the overexpression of PEX27 or PEX11 [51] The triple deletion shows a matrix protein import defect, even under conditions where peroxisome proliferation is not induced by oleic acid [51] In the triple mutant, thiolase is expressed at normal levels, indicating that Pex11 family members are not involved in fatty acid signalling Single and double deletions of members of the PPPs contain enlarged peroxisomes [51–53], underscoring the idea that Pex11 proteins are involved in peroxisome proliferation Conversely, the overexpression of each of the family members causes peroxisome proliferation or enlargement [51,52] The overexpression of PEX25 also causes kamellae around the nucleus [51] PEX25 is induced by oleic acid [53,54] through an unusual oleate response element in its promotor [54], whereas PEX27 is not induced at all on oleic acid [51,52] Thus, in oleic acid-induced cells, the Pex11 expression level is highest and the Pex27 expression level lowest All Pex11 proteins interact with themselves [51,52,55] They are likely to form homo-oligomers or homodimers Additionally, Pex25 and Pex27 interact with each other [51,52] In trypanosoma, there are also two additional Pex11 isoforms, GIM5A and GIM5B These two proteins are nearly identical in sequence and show weak similarity to Pex11 Both are  26 kDa, have two putative 5172 S Thoms and R Erdmann transmembrane domains, and assemble into hetero-dimers [56] A GIM5 reduction leads to a lower phosphatidylcholine ⁄ phosphatidylethanolamine ratio and a decrease in ether lipids [57], which could increase membrane fluidity Trypanosomes with reduced GIM5 levels have enlarged glycosomes, which are more fragile than wild-type glycosomes [57] Thus, it turns out that mammals, S cerevisiae and trypanosomes have three Pex11 homologues each Whether they represent an early or a late diversification of an ancestral Pex11 function could not be determined because of their low sequence similarity Pex11 and perilipin In mouse, PEX11a and the lipid body protein perilipin are regulated from a single PPRE that is situated between the two genes [58] As a consequence of this gene arrangement, PEX11a, which is expressed mainly in the liver, and perilipin, whose expression is limited to adipose tissue, can be competitively regulated by PPARa and PPARc, respectively This is not only a noticeable example of gene clustering in mammals [59], it also indicates that peroxisome proliferation can be induced by switching from PPARc to PPARa Furthermore, the common regulation of Pex11 and perilipin indicates metabolic association of peroxisomes with lipid storage function [60] New proteins affecting peroxisome number Pex28 and Pex29 are two recently identified proteins with a weak similarity to Pex24 from Y lipolytica Pex24 is an oleic acid-inducible peroxisomal integral membrane protein that is required for growth on oleic acid [61] Mutants of PEX24 have no apparent peroxisomes, they mislocalize peroxisomal matrix and membrane proteins, yet contain vesicular structures with some peroxisomal proteins [61] Pex28 and Pex29 from S cerevisiae are also peroxisomal membrane proteins [62] They are, however, not inducible by oleic acid Double or single deletions of the two proteins show an increased number of small and clustered peroxisomes Pex23 from Y lipolytica is an oleic acid-inducible membrane protein [63] Three proteins from bakers yeast, which have been termed Pex30, Pex31, and Pex32, show sequence similarity to Pex23 and have also been localized to the peroxisomal membrane [64] Pex30 and Pex32 are induced by oleic acid These new peroxins are partially redundant and partially interact with each other Deletions of these latest additions to the PEX list show an increase in peroxisome numbers, enlarged or clustered peroxisomes, so that they have FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS S Thoms and R Erdmann Peroxisome proliferation been described as regulators of peroxisome size and number [64] Based on an epistasis analysis, Pex30–32 are placed downstream of Pex28 and Pex29 [64] Models for Pex11 function The eight peroxins – Pex11, Pex25, Pex27, Pex28, Pex29, Pex30, Pex31, and Pex32 – have a more or less pronounced effect on peroxisome size and number To date it is unclear how this effect is exerted Different explanations are possible, as follows: (a) Some of these proteins might be directly involved in fatty acid metabolism [65] Yeast mutants lacking PEX11 exhibit a defect in the b-oxidation of mediumchain fatty acids [65] On this basis, it was suggested that Pex11 plays a primary role in medium-chain fatty acid metabolism and promotes peroxisome division only indirectly [65] In addition, there is evidence that Pex11 can promote peroxisome proliferation in the absence of metabolism [66] (b) The peroxins might be metabolite transporters or porins [57] This would, however, require a rather broad substrate specificity of these proteins, with fatty acid and glycolytic substrates being transported in classical peroxisomes and glycosomes, respectively (c) They might be structural components of the peroxisomal membrane For PPPs such an explanation is likely, yet nonexclusive with other explanations They are by far the most abundant proteins of the peroxisomal membrane (shown in yeast and trypanosomes) Thus, they might directly and specifically shape the peroxisomal membrane Overexpression of other peroxisomal membrane proteins has been reported not to induce peroxisome proliferation [66] (d) They might recruit other proteins to the membrane The recognition of Pex25 as a receptor for the GTPase Rho1 [67] could be a first step of research into this direction In summary, there are some models on how PPPs (together with Pex30 to Pex32) might affect peroxisome number These models are nonexclusive with each other, and the mechanism of action will not be the same for all PPPs In the light of the different roles that have been suggested for Pex11, it is possible that PPPs are multifunctional enzymes Recently, another class of proteins has come into focus These are suggested to affect peroxisome division in a more direct way Fig Domain structure of dynamins and dynamin-related proteins (DRPs) GED, GTPase effector domain; MD, middle domain; PH, pleckstrin homology; PRD, proline- and arginine-rich domain dynamins, (b) the structural and physicochemical properties of DRPs and (c) DRPs engaged in the division of endosymbiotic organelles Dynamins are involved in endocytosis and intracellular trafficking Dynamins are GTPases involved in intracellular fission processes [68–70] Five domains have been identified in conventional dynamins: a highly conserved N-terminal GTPase domain, a less conserved ‘middle domain’, and a pleckstrin homology domain that mediates interactions with phosphatidylinositol-phosphates (Fig 2) The C terminus comprises the GTPase effector domain (GED), which activates GTPase activity and mediates self-assembly, and a proline and arginine-rich domain (PRD) that mediates interactions with SH3 domains of effector proteins of the actin cytoskeleton Dynamins are required in phagocytosis and in caveolae- and clathrin-dependent endocytosis [71] Of the three conventional mammalian dynamins, Dynamin1 is neuron-specific, Dynamin2 is expressed in all tissues and Dynamin3 is found in brain, lung, heart, testis and blood cells The role of dynamin in clathrin-mediated endocytosis emerged from the study of the temperature-sensitive mutant shibire in Drosophila melanogaster [72] Shibire shows a paralytic phenotype that is probably caused by a defect in the reuptake of synaptic vesicles at the presynaptic membrane and subsequent synaptic vesicle depletion at the neuromuscular junction [73] Electron micrographs of shibire nerve termini show the formation of clathrin-coated buds unable to sever from the membrane Dynamin localizes to the necks of these buds [73– 75] Recently, a mutation in the PH domain of DNM2 has been identified as the cause of one form of CharcotMarie-Tooth disease, a neuromuscular degenerative disorder [76], thereby providing the first link between a classical dynamin and an inheritable human disease DRPs in peroxisome division Dynamin biochemistry and structure Before addressing the role of DRPs in peroxisome division, we will briefly introduce (a) conventional In vitro, dynamin assembles into rings upon dilution into buffers of low ionic strength [77] Furthermore, FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS 5173 Peroxisome proliferation dynamin can self-assemble into spiral-like structures around liposomes in vitro, tubulate them and, depending on the lipid composition, cause them to vesiculate [78–80] It is a matter of debate whether dynamins in vivo are involved in both the constriction and the scission of vesicular membranes [68] Dynamin has been described as a force-generating mechanochemical enzyme using GTPase-dependent conformational changes to drive fission directly either by consticting [82] or extending the necks of coated pits [82,83] These models are referred to as the ‘pinchase’ and the ‘poppase’ model, respectively [78,84] Dynamins are characterized by a low affinity for GTP and GDP, which makes them independent of a guanidine nucleotide exchange factor The GED functions as a GTPase-activating protein Upon homo-oligomerization, the GTPase activity is greatly stimulated [81], providing support for the pinchase model An alternative model is based on experiments with dynamin GED mutants that have lost GTPase-activating protein function, yet, when overexpressed in baby hamster kidney cells, stimulate endocytosis [85,86] This gave rise to the idea that dynamin, like other members of the GTPase superfamily [87] works as a molecular switch by effecting downstream activators of membrane fission processes [88] In all models on dynamin function, however, dynamin assembles at the neck of membrane invaginations that are later to be fissioned A large number of cytoskleletal proteins interact with dynamins in endocytosis, often via the PRD domain of dynamin [89–94] These include profilin, Abp1, syndapin, intersectin and cortactin Recently, it has been shown that the yeast DRP, Vps1, is also required for normal actin organization and that it interacts with the actin regulatory protein, Sla1 [95] Dynamin proteins might link the cytoskeleton to vesicles [90,92] Information on the dynamics of dynamins in vivo has been obtained by evanescent wave microscopy, which allowed a time-resolved analysis on how clathrin-coated pits move inwards from the plasma membrane In this study, a consecutive recruitment of dynamin and actin was observed [96] Thus, dynamin may be the precondition for actin assembly Recently, it has been shown that Dynamin2 functionally interacts with the actin-binding protein cortactin not only at the cell membrane but also at the Golgi apparatus [97], so that a model which unites the function of dynamin proteins at various cellular sites and their mode of interaction with the cytoskeleton now seems within reach 5174 S Thoms and R Erdmann DRPs DRPs share, with classical dynamins, the N-terminal GTPase domain, a middle domain, and the C-terminal GED (Fig 2) Obvious PRDs or PH domains are not found in DRPs Examples of DRPs are Mx proteins, mammalian DLP1, and the yeast proteins Dnm1, Mgm1 and Vps1 Mx proteins are interferon-inducible DRPs [98] Like dynamin, they self-assemble and bind and tubulate lipids, a function that might not be required for their antiviral activity Mx proteins are found in association with the endoplasmic reticulum Mx proteins are able to shield cells from infections with RNA viruses It is hypothesized that they so by binding to the viral nucleocapsid and either promoting its degradation or preventing its nuclear entry DLP1 is a mammalian DRP required for the maintenance of mitochondrial morphology and division [99,100] It is localized to mitochondria, but not exclusively [101,102] DLP1 oligomerizes and has mechanochemical properties similar to dynamin [103,104] The yeast genome does not encode a conventional dynamin Of the three DRPs, Dnm1 and Mgm1 are involved in mitochondrial fission and fusion, and Vps1 is required for peroxisome morphology and for protein trafficking to the vacuole (vacuolar protein sorting) [105–107] Vps1 also participates in clathrin-dependent trafficking from the Golgi via a prevacuolar compartment to the plasma membrane This pathway leads to the synthesis of high density secretory vesicles, and is also dependent on the SNARE Pep12 [108] DRPs in the division of endosymbiotic organelles Endosymbiotic organelles rely, for their division, on a combined machinery, which is derived partly from the host and partly from the endosymbiont [109–111] Symbiont-derived proteins include FtsZ proteins, which are GTPases FtsZ proteins might be ancient relatives of dynamins This would, however, not be supported by structural data: FtsZ is a structural homologue of tubulin [112], whereas dynamin has a different fold belonging to the GTPase superfamily [113] In mitochondria of nearly all species, the dependence on these FtsZ-type symbiont-derived cytosolic factors has been lost Two of the three yeast DRPs, Dnm1 and Mgm1, are involved in mitochondria morphology and inheritance Mgm1 is required for mitochondrial inner membrane fusion [114,115] Defects in its human homolgue, OPA1, are associated with optical atrophy type I [116,117] Mgm1 is present in two essential isoforms in FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS S Thoms and R Erdmann the intermembrane space of mitochondria The shorter isoform is derived from the longer by processing [118,119] by the rhomboid protease Pcp1 [120] The two GTPases, Fzo1 and Mgm1, are linked on the outer mitochondrial membrane by Ugo1 [121] Dnm1 is involved in mitochondrial fission [122,123] and can be regarded as an counterplayer of Fzo1, which might also be a distant relative of dynamin Loss of Dnm1 leads to the formation of a mitochondrial net throughout the yeast cell, whereas loss of Fzo leads to mitochondrial fragmentation as a result of uncompensated mitochondrial fission [124–126] At the division site of mitochondria, Dnm1 forms a complex with the WD protein, Mdv1 [127,128], and the TPR protein, Fis1 [129,130] Recently it has become possible to study yeast mitochondrial fusion in vivo [131] The double membrane of mitochondria necessitates a complex node of division, with many GTPases working together Peroxisomes might offer a simpler system for studying the action of DRPs ARC5 is a DRP required for chloroplast division [132] It is localized to a ring at the chloroplast division site and might represent the  nm outer-plastiddividing ring Mutants of ARC5 have a reduced number of enlarged, dumbbell-shaped chloroplasts [133] Interestingly, they are still constricted, but cannot divide [134] Similarly to DLP1, DRP-1, the DLP1 homologue of Caenorhabditis elegans is involved in the scission of the mitochondrial outer membrane [135] DRP-1 is further required to induce mitochondrial fragmentation and programmed cell death (PCD) [136] The overexpression of DRP-1 can induce PCD, indicating an evolutionary conservation of mitochondrial involvement in PCD The yeast homologue of DPR-1, Dnm1, might also be involved in PCD [137] The parasitic eukaryote T brucei contains only a single mitochondrion, which undergoes extensive remodelling during the life cycle of the trypanosome The genome of T brucei, however, like those of Leishmania major and T vivax, encodes only a single dynamin, which is required for mitochondrial fission and not for endocytosis [138] This points to an original role of dynamins in organelle division, rather than endocytosis At the same time it suggests that all dynamin-dependent organelles of these eukaryotes would have to rely on the same dynamin for division DRPs in the division of peroxisomes The mammalian DRP, DLP1, partially localizes to peroxisomes and is involved in peroxisome fission Its peroxisomal localization is more readily visible when FEBS Journal 272 (2005) 5169–5181 ª 2005 FEBS Peroxisome proliferation peroxisome proliferation is induced by the overexpression of PEX11b [139,140] DLP1 is also found in immunopurified peroxisomes [140] and is enriched in the peroxisomal fraction when peroxisome proliferation is stimulated by bezafibrate [139] Fis1, a DLP1-interacting protein, known to function in mitochondrial fission, was also found to play a role in peroxisomal fission, and might act as an adaptor for DLP1 [140a] Overexpression of the dominant negative K38A GTPase domain mutation of DLP1 (which inhibits GTP hydrolysis, but does not affect GTP binding) leads to pronounced tubulation of peroxisomes when PEX11b is co-expressed [139] Inhibition of DLP1 by expression of the dominant negative form of DLP1 also affects the morphology of mitochondria, but did not change the distribution of peroxisomes in the cell [139] For the overexpression of a S39N mutation in the GTPase domain (reduced GTP affinity) in a DLP1 isoform, a reduction in peroxisome number has been reported, whereas overexpression of wild-type DLP1 has no effect on peroxisome abundance [140] To a lesser extent, peroxisome tubulation was also observed when PEX11b was not overexpressed [139] An RNAi knock-down of DLP1 in COS-7 (green monkey kidney) cells leads to elongated peroxisomes with a segmented appearance [141], whereas an RNAi knock-down of DLP1 in immortalized human fibroblast cells leads to a reduction in peroxisome abundance [140] In the absence of DLP1, peroxisomes are still able to constrict, yet not able to divide, suggesting that the DRP DLP1 is required for division, but not for constriction [141] Concomitant overexpression of PEX11b induces further elongation of peroxisomes and results in what appears to be a peroxisomal network [141] However, when DLP1 was reduced by RNAi, overexpression of PEX11b could no longer induce peroxisome proliferation [140] In summary, DLP1 seems to be involved in the fission of peroxisomes Overexpression of PEX11 causes peroxisome division in a multistep process with elongation first, and then division DLP1 is believed to be required for the division step only (Fig 1) The involvement of a DRP in peroxisome division was first observed in yeast [142] A deletion mutant of VPS1 contains only a few enlarged peroxisomes (Fig 3), which, by electron microscopic analysis, appear as ‘beads on string’, that is, constricted organelles before fission [142] A partial co-localization of Vps1 with peroxisomes has been observed [142] DLP1 shows a higher sequence similarity to yeast Dnm1 than to Vps1; however, Dnm1 does not influence peroxisome division under normal growth conditions 5175 Peroxisome proliferation Fig Peroxisomes in a yeast Dvps1 knockout Glucose-grown Saccharomyces cerevisiae wild-type and Dvps1 knockout cells expressing yEGFP-SKL (a C-terminal fusion of a peroxisomal targeting signal type1 to yeast enhanced green fluorescent protein) were analyzed by fluorescence microscopy [142,143] Together with Vps1, actin [142] and the type V myosin, Myo2, are required for peroxisome inheritance [142] DRP involvement in peroxisome fission is also found in plants In the Arabidopsis thaliana DRP3A mutants, peroxisomes are elongated and reduced in number [144] These mutants also show an aberrant mitochondrial morphology [144] Co-operation of PPPs and DRPs? Interestingly, a double deletion of PEX28 and PEX29 can be complemented by the overexpression of Vps1 or Pex25, indicating a genetic interaction of members of the two protein families [62] However, loss of the DRPs DLP-1 or Vps1 has a more stringent effect on peroxisome number reduction than the loss of Pex11 Conversely, Pex11 overexpression can induce peroxisome proliferation, whereas DRP overexpression does not have such an effect Based on these findings, it may be speculated that DPRs are part of the peroxisome division machinery, whereas Pex11 family members act earlier by causing membrane elongation or recruitment of components of the division machinery (Fig 1) However, attempts to demonstrate a physical interaction between PPPs and DRPs have not yet been successful [140] Thus, if there is a physical interaction between PPPs and DRPs it is probably indirect or transient Knowing that DRPs are generally involved in organelle division, and observing that the disruption of DRP1 or Vps1 leads to peroxisome enlargement, it may seem an obvious interpretation that these proteins are required for peroxisome division This interpretation, however, is based on the assumption that 5176 S Thoms and R Erdmann peroxisomes arise by growth and division, rather than by de novo biogenesis from heterologous intracellular membranes In the light of peroxisome biogenesis in association with the secretory pathway [16], and DRPs being mainly localized to the endoplasmic reticulum and to the Golgi apparatus, it is possible that DRPs are not primarily involved in peroxisome division, but also in the biogenesis from peroxisomes as they emanate from their precursors In this scenario, the steps leading to peroxisome formation depicted in Fig would reflect peroxisome biogenesis rather than peroxisome division Dynamins have been given a central role in the evolution of the eukaryotic cell [109] Likewise, Pex11 proteins might share a long evolutionary history [145] Thus, elucidation of the roles of these proteins in peroxisome function will be of interest to cell biologists and evolutionary biologists alike Acknowledgements We thank Michael Schrader and Hartmut Niemann for reading the manuscript This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB642 and ER178 ⁄ 2-4) and by the Fonds der Chemischen Industrie References van den Bosch H, Schutgens RB, Wanders RJ & Tager JM (1992) Biochemistry of peroxisomes Annu Rev Biochem 61, 157–197 Thoms S & Erdmann R (2005) Import of proteins into peroxisomes Protein Movement Across Membranes (Eichler J, ed.) 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