Peroxisome Biogenesis: Something Old, Something New, Something Borrowed

Fred D. Mast, Andrei Fagarasanu, Barbara Knoblach, Richard A. Rachubinski


Eukaryotic cells are characterized by their varied complement of organelles. One set of membrane-bound, usually spherical compartments are commonly grouped together under the term peroxisomes. Peroxisomes function in regulating the synthesis and availability of many diverse lipids by harnessing the power of oxidative reactions and contribute to a number of metabolic processes essential for cellular differentiation and organismal development.

The diversity of tissues and organs within the bodies of complex organisms is a reflection, at least in part, of the diversity of cell types they contain. One challenge in physiology is determining how the basic building blocks common to all cells can be reconfigured to provide the myriad of cell types and tissues found in complex organisms. Although peroxisomes are a ubiquitous constituent of eukaryotic cells, they also display cell type-specific characteristics that can aid in producing this diversity. Peroxisomes are remarkably plastic in both their metabolic functions and their response to environmental stimuli, and they display properties that position them as key regulators of many biochemical pathways. In this review, we place our current progress in understanding peroxisome biogenesis and function within a larger historical perspective to highlight many of the ideas and findings that shape our knowledge of this organelle.

The Peroxisome Concept

Christian de Duve coined the term “peroxisome” to help explain the observed cosedimentation of a group of hydrogen peroxide-producing oxidases and catalase in equilibrium density gradient centrifugation (5, 10, 11). The functional coupling of these two enzymes creates an environment in which the oxidase-mediated production of hydrogen peroxide is harnessed by catalase to oxidize a second substrate through mediated peroxidation, resulting in the controlled decomposition of hydrogen peroxide into water and molecular oxygen. The substrate specificity of the peroxisomal oxidases is fairly specific (127, 131), and in humans, depending on the cell type, peroxisomes contain oxidases specific for, among others, fatty acyl-CoAs, D-amino acids, spermidine, and L-pipecolic acid (133). Substrates for catalase exhibit a much broader range and include alcohols like ethanol and methanol, certain phenols, formaldehyde, formic acid, and the nitrite ion. In the absence of a suitable substrate, catalase can mediate the direct peroxidation of hydrogen peroxide using another hydrogen peroxide molecule. Irrespective of the substrates involved, the net oxygen consumption of oxidase-/catalase-coupled reactions can be positive, negative, or neutral depending on the availability of substrate for catalase and the specific oxidases coupled to it, which may be cell type-specific. Oxygen consumption by peroxisomes is high, reaching levels of 20% of the total oxygen consumed by the liver of rat (7). Several groups have proposed that this high level of oxygen consumption by peroxisomes positions them to serve as both a generator and buffer of reactive oxygen species (ROS) (see Ref. 2, 108).

Curiously, oxidases and catalase do not need to colocalize for a coupled reaction to occur. For example, catalase in peroxisomes may assist in degrading hydrogen peroxide produced by NADPH oxidase, which is found at the plasma membrane and has been implicated in the generation of ROS for the respiratory burst of neutrophils (69, 139). Therefore, it is the combination of an oxidase and catalase enclosed by the distinct lipid bilayer of peroxisomes that forms the basis of what de Duve labeled the “peroxisome concept” (10). The peroxisomal membrane represents an essential part of this concept, forming a selectivity barrier that provides an important level of regulation for the transport of substrates and metabolites as well as the peroxisomal enzymes themselves. In addition to catalase and the oxidases, peroxisomes also contain over 50 other enzymes that enable them to metabolize both very-long-chain fatty acids and branched-chain fatty acids, which in their turn makes peroxisomes an important site for the synthesis of bile acids and plasmalogens (Ref. 135; see Ref. 133 for a thorough discussion of peroxisome biochemistry). Peroxisomes also act as cellular detoxifiers. In the liver, peroxisomes can couple the β-oxidation of fatty acids and bile acid precursors with the oxidation of ingested ethanol to acetaldehyde to account for as much as 50% of the total metabolism of ethanol when substrates for the H2O2-producing oxidases are present in excess (8, 85, 120). In the kidney, peroxisomes couple the oxidation of L- and D-amino acids to the oxidation of harmful molecules filtered from the blood, such as lipid-based xenobiotics. And in glial cells, peroxisomes are thought to regulate ROS availability together with plasmalogen synthesis (51).

The Role of Peroxisomes in Lipid Metabolism

Peroxisomes, together with the endoplasmic reticulum (ER) and mitochondria, function as the primary sites of lipid metabolism in the cell (FIGURE 1). The interdependence of these organelles is illustrated by the requirement for the transfer of the activated variants of branched and very-long-chain fatty acids from the mitochondria or ER to peroxisomes. For example, phytanic acid, a branched-chain fatty acid present in the human diet and requiring a round of α-oxidation before subsequent rounds of β-oxidation, can be activated in the ER, mitochondria, or peroxisomes by fatty acyl-CoA synthetases found in all three compartments (132). Activation of phytanic acid requires its transfer across the membranes of the ER or mitochondria to peroxisomes where its catabolism occurs. Furthermore, disrupting peroxisome formation alters the metabolism of cholesterol in the ER and results in the accumulation of cholesterol esterified to very-long chain fatty acids, as observed in mutant mice that fail to assemble functional peroxisomes (56, 57). Conversely, peroxisomal β-oxidation of very-long-chain fatty acids does not proceed to completion in the peroxisome, and partially oxidized fatty acyl-CoA intermediates are shuttled to the mitochondria to generate energy (reviewed in Ref. 93).


The interdependence of peroxisomes, ER, and mitochondria in lipid metabolism

Defects in peroxisome function usually result in the accumulation of unused peroxisomal metabolites. In assaying the plasma of patients with a peroxisome biogenesis disorder for increased levels of the bile acid precursors di- and trihydroxycholestanoic acid, Wanders and colleagues also identified a C29-dicarboxylic acid that is not present at significant levels in the serum of normal individuals (18). They and others have postulated that the accumulation of this compound results from an aberrant reaction involving C27, trihydroxycholestanoic acid (18, 46, 86). The accumulation of these and other lipid molecules typically metabolized by peroxisomes is thought to contribute to the many and pleiotropic defects exhibited by individuals with peroxisome dysfunction (reviewed in Ref. 114). In the original description of Zellweger syndrome, a severe genetic disorder in which patients die early in infancy due to their inability to form functional peroxisomes, cells of patients were reported to have reduced capacity for mitochondrial respiration (26). This observation may also explain the phenotypic diversity exhibited by patients within the same complementation group of a peroxisome biogenesis disorder, since the ability of cells to withstand stress resulting from the accumulation of peroxisomal metabolites depends to a greater or lesser extent on the different genetic makeups of individuals and the environments in which they live (78, 97).

Peroxisome Biogenesis

Peroxisomes are formed and maintained through the concerted efforts of a group of proteins called peroxins that are encoded by PEX genes and have roles in the formation and maintenance of peroxisomes (12). The finding that the products of a distinct collection of genes function in the biogenesis of peroxisomes refines de Duve's classical definition of a peroxisome to include the essential contribution of these PEX genes. Our understanding of the specific roles of individual peroxins in both peroxisome biogenesis and in other aspects of cell biology is still at a rather rudimentary level, and the proposed roles of many peroxins still rely heavily on the pleiotropic phenotypes of peroxisomes and cells that result from their mutation. Peroxisome biogenesis is also stimulated by the expression of genes that encode peroxisomal enzymes and whose transcription is regulated by changes in the metabolic requirements of cells (33, 110).

Peroxisome Growth and Division

Cells expand their peroxisomal population by growth and division of peroxisomes (62, 80). Peroxisomes are homeostatic organelles that monitor the levels of their matrix proteins and divide only after a particular threshold has been reached (32). In the yeast Yarrowia lipolytica, sequestration of the peroxisomal membrane protein Pex16p by the matrix enzyme fatty acyl-CoA oxidase results in a cascade of events that leads to the production of diacylglycerol, which promotes positive membrane curvature and the recruitment of peroxisome division factors (31, 32). Threshold appears to be relative, because the diameter of individual peroxisomes ranges from 0.1 to 1 μm. Several factors involved in peroxisome division are shared with other organelles. These factors, which include dynamin-like proteins and their associated recruitment factors, may function to coordinate the division of peroxisomes with other cellular processes (106). In Saccharomyces cerevisiae, the dynamin-related proteins Dnm1p and Vps1p were shown to differentially regulate peroxisome division because their recruitment to peroxisomes is mediated by nonoverlapping factors (31, 79, 80, 129). In the case of Dnm1p, its recruitment factors, i.e., Fis1p, Mdv1p, and Caf4p, are shared between peroxisomes and mitochondria (79). Cells of a patient deficient in the dynamin-like protein, Dlp1, the human homolog of Dnm1p, also exhibited defects in both mitochondrial and peroxisomal division (134). Fis1 appears to recruit Dlp1 to both compartments (55). Together, these findings suggest that more than one mechanism can signal and execute organelle division. Studies in S. cerevisiae showed that abrogation of peroxisome division occurred only in triple deletion cells lacking Dnm1p,Vps1p, and Inp2p, which is the peroxisome-specific receptor for the molecular motor, Myo2p, and a key regulator of peroxisome inheritance in this yeast (80). These findings support a contribution of mechanical forces to the final scission of peroxisomes and implicate cell cycle cues in linking the growth of peroxisomes to overall cell growth and division. Currently, two modes of peroxisome division are envisioned, one guided by the need to proliferate peroxisomes in response to environmental stimuli, i.e., a diet rich in substances requiring metabolism by peroxisomes, and one guided by a cell's need to replicate its organelle population in response to cell division (15, 42). Peroxisome division appears also to be required for proper metabolic function, although this requirement is not absolute. Mice lacking PEX11β, which is involved in regulating peroxisome division, exhibit the classic hallmarks of Zellweger syndrome but, surprisingly, are normal in their ability to metabolize very-long-chain fatty acids, suggesting that the lack of PEX11β results in a defect in some yet uncharacterized metabolic function of peroxisomes (65). In S. cerevisiae, pex11Δ cells display defects in β-oxidation, particularly of medium-chain fatty acids (14, 126); however, the mechanism underlying these defects remains controversial (66). Recently, a pex11Δ mutant of the yeast Pichia pastoris was shown to have a defect in the unconventional secretion of acyl-CoA binding protein (70), but this was shown to be due to a defect in peroxisomal metabolism rather than to a direct contribution of Pex11p to the secretion of the protein.

One undetermined aspect of peroxisome division is whether it is symmetrical, asymmetrical, or both (FIGURE 2). Evidence for asymmetrical division has come from electron micrographs showing dimples or tubules emanating from the body of the peroxisome (14, 20). Also, in the yeast Hansenuela polymorpha, peroxisomes were observed to divide asymmetrically with the formation of a prominent tubule emanating from the body of the peroxisome (82). Asymmetry is not restricted to the peroxisome body but is also seen in constituents of the peroxisomal membrane. The membrane protein Inp2p is polarized toward the leading edge of peroxisomes in yeast cells lacking the dynamin-related protein Vps1p (16). Matrix proteins can also show an asymmetrical distribution, as in the case of rat acyl-CoA oxidase, which is often asymmetrically distributed between the two peroxisomes arising from peroxisome division (136). The asymmetrical distribution of lipids within the peroxisomal membrane is an important aspect of the current model of peroxisome division in Y. lipolytica (6, 31, 32). Studies have shown that Pex11p may oligomerize (72, 99, 118) to form a tubule by elongating a portion of the peroxisome in an asymmetrical manner (59). However, contrarily, overexpressed Pex11p/PEX11β constricts peroxisomes symmetrically, giving rise to peroxisomes with a dumbbell or beads-on-a-string appearance (14, 54). Yeast cells lacking Vps1p also have peroxisomes with a beads-on-a-string appearance, with constrictions regularly spaced along the elongated axis (44).


Peroxisome division

Peroxisome division can be symmetrical or asymmetrical. After receiving a signal to divide, peroxisomes elongate and are constricted into divisible units, making them competent for the final scission event. Whether symmetric or asymmetric division represents the primary mode of peroxisome division and whether peroxisome division, irrespective of the mode of cleavage, leads to matrix protein asymmetry remain unresolved.

The importance of peroxisome division is reflected in another prominent aspect of peroxisomes, their heterogeneous nature. Liver peroxisomes isolated from rats treated with the hypolipidemic drug clofibrate showed the presence of a distinct population of peroxisomes that were less dense than mature peroxisomes but still import competent for the matrix enzyme, acyl-CoA oxidase (38). Similar observations were made in individual cells of a human hepatoblastoma cell line (107). Erdmann and Blobel provided a temporal justification for the conversion of peroxisomes of light density to peroxisomes of heavy density as a response of yeast to growth on oleate, which activates the transcription of oleate-responsive genes and increases the import of matrix proteins so that peroxisomes “mature” (14). Remarkably, Titorenko and Rachubinski demonstrated six biochemically and morphologically distinct peroxisomal populations in Y. lipolytica (121). Together, these findings show that, although peroxisomes behave essentially as individual entities that form and function in relative seclusion to one another, they can be timed for synchronous development depending on environmental factors, e.g., nutrient availability. These findings also support the concept that mature peroxisomes do not fuse with each other, although the fusion of immature, precursor peroxisomes may play a role in their development (121). Therefore, organellar fusion apparently does not help maintain the metabolic functionality of peroxisomes as it does for mitochondria (39). Also, in contrast to mitochondria (40), mature peroxisomes were not observed to fuse in yeast mating assays (80).

De Novo Peroxisome Biogenesis

Peroxisomes rely on essential contributions from the ER to support their growth and division. This reinterpretation of the growth and division model of peroxisomes is significant because it now positions peroxisomes as a specialized branch or extension of the secretory system (105). The first mechanistic support for an ER contribution to peroxisome biogenesis came from studies in Y. lipolytica showing that mutations in the signal recognition particle constituent, Srp54p, or deletion of another gene required for secretion, SEC238, resulted in defective peroxisome biogenesis and the accumulation of the peroxisomal membrane proteins, Pex2p and Pex16p, in the ER (122, 123). In addition, Pex2p and Pex16p were shown to normally contain N-linked core glycosylation, unequivocally demonstrating that the branch point to peroxisomes in the secretory system was at the level of the ER. It has been proposed that this contribution of the ER underlies the reemergence of peroxisomes in cells from peroxisome biogenesis disorder patients on complementation of the defective gene (52, 75, 112). The contribution of the ER to peroxisome biogenesis was also demonstrated by studies of the peroxins Pex3p and Pex19p. Absence of Pex3p or Pex19p results in a complete mislocalization of peroxisomal matrix and membrane proteins (41). Working in yeast, Hoepfner and colleagues asked the simple question, “What happens when Pex3p and Pex19p are added back?” They showed that when Pex3p was reintroduced into pex3Δ cells, it first sampled the ER and then sequestered into distinct subdomains that went on to become functional peroxisomes (43). This ability of Pex3p to sort through and exit the ER was shown to depend on Pex19p, and an ER-localized pool of Pex3p that accumulated in pex19Δ cells could form peroxisomes upon reintroduction of Pex19p (43). These results were taken as evidence that peroxisomes form de novo from the ER. Further support for the de novo synthesis of peroxisomes came from work in mammalian cells. Kim and colleagues observed that cells lacking peroxisomes because of mutation of the PEX16 gene could form peroxisomes upon reintroduction of the gene (52). In an elegant experiment employing photoactivatable GFP, they showed that peroxisomes appeared to form de novo rather than by division (52).

It must be said that all the aforementioned findings cannot unequivocally exclude division as the sole or principal mechanism underlying the maintenance or growth of the peroxisome population in wild-type cells. Indeed, the contribution of central players in the secretory pathway, such as COPI and COPII (61, 87, 88, 113, 130) and the ER translocon channel protein, Sec61p (88, 111), to peroxisome biogenesis remains uncertain, although components of the DSL1 complex involved in retrograde transport between the Golgi complex and the ER have been shown to be involved in peroxisome biogenesis in yeast (88). In effect, it has been uncharitably argued that de novo peroxisome biogenesis is an anomalous yet fortunate response to a complete and catastrophic loss of peroxisomes from cells and not a normally occurring event in nature (62). It remains for investigators to provide an unequivocal demonstration of the role of de novo peroxisome biogenesis in “normal” cells under “normal” conditions.

Peroxisomal Membrane Protein Trafficking

To understand how proteins are inserted into the peroxisomal membrane, it is important to consider that all peroxisomal proteins are acquired posttranslationally by the peroxisome (2123, 27, 45, 94, 100). This observation played a crucial role in rejecting a contribution of other organelles to peroxisome biogenesis (23, 63). However, a conundrum remains as to how peroxisomal membrane proteins (PMPs) are inserted into and anchored within the peroxisomal membrane. Membrane proteins of the secretory pathway rely on the Sec61p translocon to passage certain portions of their sequence through the ER membrane and also to imbed their hydrophobic transmembrane domains within the membrane (96). Similarly, mitochondria have translocons in their inner and outer membranes to aid in the insertion of the hydrophobic segments of proteins into these membranes (9). As for peroxisomes, Pex3p and Pex19p have been shown to be essential for targeting membrane proteins to peroxisomes (41). siRNA-mediated knockdown of Pex19p impairs the import of membrane proteins into peroxisomes and decreases their half-lives (47, 100). PMPs contain a divergent hydrophobic sequence known as the membrane peroxisomal targeting sequence (mPTS) that is bound by Pex19p in the cytosol (34, 98). Pex19p bound to a cargo PMP docks to Pex3p on the peroxisomal membrane (17) and, in a poorly understood process, facilitates the insertion and orientation of the PMP into the peroxisomal membrane (37). Pex16p in mammalian cells has been proposed to substitute for Pex3p as the Pex19p docking site of a second class of PMPs that do not rely on Pex3p for their targeting (74). Interestingly, the entire process of protein integration into the peroxisomal membrane is apparently energy-independent, not requiring ATP or GTP hydrolysis (89).

Might Pex3p, Pex16p, and Pex19p associate to form a translocon that would help in overcoming the energy barrier to insertion expected both for a protein that spans a membrane once and especially for a protein that spans the membrane multiple times and requires the passage of alternating hydrophobic and hydrophilic regions across a lipid bilayer? Pex19p is farnesylated at its COOH terminus, which could aid in disrupting the membrane lipid bilayer and/or stabilizing the hydrophobic transmembrane domain of a nascent PMP (28). But farnesylation is dispensable for Pex19p function (128). Moreover, there is no evidence that Pex3p or Pex16p can form channels in membranes either alone or in combination with each other. Alternative strategies for the incorporation of PMPs into membranes include use of the ER translocation apparatus and/or the mitochondrial outer membrane translocase, followed by a trafficking event from these membranes to the membranes of peroxisomes. There is an ever lengthening list of PMPs that have been shown to traffic through the ER (4, 24, 35, 43, 52, 58, 117, 123, 137). As previously mentioned, Pex16p is a glycosylated protein in Y. lipolytica (123) that is cotranslationally inserted into the ER (52). The NH2 termini of several PMPs, including notably Pex3p, have been demonstrated to be sufficient both for their targeting to and insertion into the ER and for their subsequent travel from the ER to peroxisomes (4, 35, 117). Interestingly, the demonstration of a distinct insertion pathway for proteins with a transmembrane domain at their extreme COOH termini revealed that the tail-anchored PMP, Pex15p, also relies on this system for its insertion into membranes (109). What is currently unknown is whether the Get system is an exclusive resident of the ER or whether it is also present on the peroxisomal membrane. Using mitochondria for PMP biogenesis is a particularly attractive alternative with regard to the mitochondrial metabolite transporters that have been localized to the peroxisome membrane (3). One transporter, carnitine palmitoyltransferase (CPT1), has been shown to localize to the ER, mitochondria, and peroxisomes (19). The CPT1 in mitochondrial and peroxisomal membranes but not the CPT1 in ER membranes appears to have undergone an NH2-terminal cleavage, suggesting that mitochondria may be able to modify peroxisome function in cells by equipping peroxisomes with key metabolite transporters. The recent discovery of a vesicular mode of communication from mitochondria to peroxisomes provides a mechanism for the routing of these transporters between the two organelles (84). Thus a complex model of PMP biogenesis has emerged (FIGURE 3) that will require extensive and careful analysis to define the actual sequence of events involved in the targeting and insertion of the different and varied PMPs.


Protein insertion into the peroxisomal membrane

Translation of all peroxisomal membrane proteins begins in the cytosol, where the pathway diverges into those proteins destined for cotranslational insertion into the ER and those relying on posttranslational insertion pathways. Cotranslational insertion into the ER is mediated by the signal recognition particle (SRP) pathway. Posttranslational insertion of proteins into the peroxisomal membrane can be achieved through four routes: HSP70/HSP40 chaperones can maintain membrane proteins in an insertion-competent state and direct proteins to either the ER translocon or the translocase of the outer mitochondrial membrane (TOM) complex; COOH-terminally anchored proteins rely on the guided entry of tail-anchored proteins (Get) pathway for entry into the ER. Import into both the ER and mitochondria necessitates the existence of a trafficking mechanism to bring these PMPs to peroxisomes, which is not depicted here. PMPs can also target to the peroxisome using the PMP-specific cytosolic chaperone, Pex19, and its two docking partners, Pex3 and Pex16.

Peroxisomal Matrix Protein Import

Two types of sequences that target proteins to the peroxisomal matrix have been described: a COOH-terminal serine-lysine-leucine variant known as peroxisomal targeting signal (PTS) 1 (29) and a NH2-terminal nonapeptide known as PTS2 (116). Each sequence is recognized in the cytosol by its own cognate receptor, Pex5p for PTS1 and Pex7p for PTS2 (73, 91). Receptor-cargo complexes then dock at the peroxisomal membrane and cross the lipid bilayer. This process has been termed an “extended shuttle” because the receptor translocates together with its cargo into the peroxisomal matrix (95). The receptors are then monoubiquitinated or polyubiquitinated and exit the peroxisome to be recycled for another round of cargo import or to be degraded by the proteasomal system, respectively (64, 68, 90, 92). The PTS1 and PTS2 import pathways converge at the peroxisomal membrane through docking to Pex13p and Pex14p. In yeast, PTS2 import has been shown to favor docking to Pex13p, whereas PTS1 cargo-laden Pex5p can bind directly to Pex14p (30, 76). It has been observed that peroxisomes can differ in their concentrations of Pex13p and Pex14p within an individual cell and between cell types (49, 83), and therefore peroxisomes may specialize for particular metabolic functions by their different capacities for PTS1 and PTS2 import. However, the ability of peroxisomes to specialize based on differential PTS1 and PTS2 import is probably limited, since most peroxisomal matrix proteins contain PTS1s (115).

The ability of a soluble protein to gain access to the peroxisomal matrix is not dependent on it having a PTS, and proteins have been shown to interact with the peroxisomal matrix protein receptors in a non-PTS-dependent fashion (125). Even more striking is the ability of peroxisomes to import proteins that lack a PTS but that can piggyback on a protein containing a PTS via protein-protein interaction (25, 119, 138). Indeed, peroxisomes are unique in their ability to import fully folded and even very large oligomeric protein complexes into their matrix. The capacity of the peroxisome to accommodate large oligomeric protein structures and translocate them into the matrix is due to the proposed ability of Pex14p to associate with cargo-laden Pex5p to form a highly dynamic and expandable pore called the peroxisomal importomer (76). In theory, the unique properties of the peroxisomal importomer position the peroxisome as a central regulator of a cell's metabolic potential through its ability to modulate the distribution of key metabolic enzymes between the cytosol and the peroxisome. For example, in S. cerevisiae, Gpd1p and Pnc1p, two proteins that modulate chromatin remodeling and NADH levels in the cell, are differentially regulated in their subcellular location among the nucleus, cytosol, and peroxisomes (1, 48). In mammalian cells, malonyl-CoA decarboxylase localizes to both the cytosol and peroxisomes depending on metabolic need (101). A key challenge in interpreting the proteomes of mammalian peroxisomes has been the apparent contamination of enriched peroxisomal fractions with proteins that have other well characterized subcellular localizations (104). However, are these proteins actually contaminants of peroxisomes or are they true peroxisomal residents? An answer to this question is important for understanding how peroxisomes can influence cellular metabolism by regulating their protein complement through regulated protein import.

Peroxisomes Are All Not Equal

Although all peroxisomes share common mechanisms guiding their biogenesis, division, and protein import, peroxisomes in different cell types and in different organisms host different metabolic pathways and perform different functions. As mentioned earlier, mammalian peroxisomes have been shown to vary in their enzymatic compositions in the different organs, which helps them to perform their specific metabolic roles. Peroxisomes have also specialized to help organisms adapt to their specific environmental niches. One example is found in the Trypanosomatidae, which contains specialized peroxisomes called glycosomes that house enzymes of the glycolytic cycle for energy production in the oxygen-poor environment of the bloodstream (77). In plants, three specialized peroxisomes have been described that have distinct roles in fatty acid β-oxidation, the formation of succinate by the glyoxylate cycle, or photorespiratory glycolate metabolism (36). Peroxisomes can also specialize to perform nonmetabolic functions. In some filamentous fungi, a specialized peroxisome plugs the septal pore between cells when the cell wall has been damaged and cytoplasm begins to bleed through it. Called Woronin bodies, these specialized peroxisomes form by the asymmetric division of a small number of peroxisomes that have imported the protein Hex1p, which is essential for the formation of Woronin bodies (67).

Some Final Thoughts

Peroxisomes have never failed to surprise in their ability to do different things and to do things differently–their specialized metabolic pathways, their distinctive mechanisms of growth and division, their highly dynamic and flexible protein import machinery, and their ability to exchange and share biogenic and metabolic factors with the ER and mitochondria. Where should we look for even more surprises? Cellular regulation of, and response to, lipid-based signaling pathways, such as the peroxisome proliferator-activated receptor pathway, is an exciting area for continued exploration (50). Also, the nature of the interrelationship between peroxisomes, the ER, and mitochondria promises new insights into the contribution of these organelles to cell physiology. The genetic tractability of model organisms, such as yeasts and fungi, have facilitated the identification of several proteins involved in maintaining peroxisome populations but currently have no known homologs in higher eukaryotes, including humans. Discovery and characterization of their predicted homologs and/or paralogs would enable a greater understanding of human peroxisome biology. Finally, the emerging view of peroxisomes as a stage or platform for orchestrating and organizing cellular responses to a variety of environmental challenges promises to provide a more nuanced appreciation of the complexity and diversity of function achievable by peroxisomes and, by extension, eukaryotic cells (13, 53, 102, 103, 124). One does not need a crystal ball to see an exciting future for peroxisomes.


We apologize to those investigators whose research could not be cited owing to space constraints.


  • F. D. Mast is a Vanier Scholar of the Canadian Institutes of Health Research and the recipient of a Studentship from the Alberta Heritage Foundation for Medical Research. A. Fagarasanu is the recipient of a Ralph Steinhauer Award of Distinction. R. Rachubinski is an International Scholar of the Howard Hughes Medical Institute. Research in the Rachubinski Laboratory is supported by grants 9208, 15131, and 53326 from the Canadian Institutes of Health Research.

  • No conflicts of interest, financial or otherwise, are declared by the author(s).


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View Abstract