Dynamics of peroxisome assembly and function

doi:10.1016/S0962-8924(00)01865-1

Trends in Cell Biology

Volume 11, Issue 1, 1 January 2001, Pages 22-29

https://doi.org/10.1016/S0962-8924(00)01865-1 Get rights and content

Abstract

Recent studies in human cells and in the yeast Yarrowia lipolytica have shown that peroxisomes consist of numerous structurally distinct subcompartments that differ in their import competency for various proteins and are related through a time-ordered conversion of one subcompartment to another. Our studies have implicated the fusion of small peroxisomal precursors as an early event in the multistep assembly of peroxisomes operating in Y. lipolytica. Newly discovered unexpected roles for peroxisomes in specific developmental programs have expanded the remarkable plasticity of peroxisomal functions. Here, we highlight recent discoveries on the highly dynamic nature of peroxisome assembly and function and suggest questions for future research in these areas.

Section snippets

Peroxisomes assemble by a multistep pathway

Early studies demonstrated heterogeneity in the population of mammalian and yeast peroxisomes in terms of their density, protein composition and protein import competency 9., 10., 11., 12., 13.. Elegant pulse-chase experiments revealed that mammalian peroxisomes of low buoyant density could convert to peroxisomes of high buoyant density ⁹. Some of the first evidence showing that the targeting of various matrix proteins and the bulk of phospholipids to peroxisomes of low density is required for

Mechanism of peroxisome fusion

Fusion of the small peroxisomal vesicles P1 and P2, the earliest intermediates in the peroxisome assembly pathway of Y. lipolytica, has recently been reconstituted in vitro 7., 8.. In vitro fusion of P1 and P2 leads to the formation of larger and more dense peroxisomes, P3 ⁷. A comparison of the biochemical and morphological properties of P3 isolated from wild-type cells with those of P3 formed by the in vitro fusion of P1 and P2 has provided evidence that the in vitro fusion reaction

Selective protein import by different peroxisomal subforms

Numerous aspects of peroxisomal protein import have recently been highlighted 15., 24., 25., 26., 27.. Studies on a variety of organisms have led to the characterization of conserved targeting signals for peroxisomal matrix and membrane proteins 5., 34., 35., 36., 37. and to the identification of 23 peroxins involved in peroxisomal protein import and biogenesis ³⁷. Analysis of the physical interactions between peroxins has inspired several models of peroxisomal protein import 5., 34., 35., 36.,

Replenishing early intermediates of the peroxisome assembly pathway

What endomembrane compartment might serve as a source for the early intermediates P1 and P2 of the peroxisome assembly pathway operating in Y. lipolytica (Fig. 1) and of pre-peroxisomes in human fibroblasts (Fig. 2)? These peroxisomal precursors are unlikely to be formed by budding from mature peroxisomes as peroxisomes can reappear in yeast 40., 41., Chinese hamster ovary (CHO) ³⁶ and human 3., 4., 42. cells lacking any recognizable peroxisome-like structures following reactivation or

A link between peroxisomes and specific developmental programs

After almost four decades of study, it appeared that the various peroxisomal functions had been completely inventoried, as described in numerous reviews 51., 52., 53., 54., 55. and cell-biology textbooks ¹. Peroxisomes typically contain at least one hydrogen peroxide-producing oxidase, and catalase to decompose the hydrogen peroxide ⁵⁶. Peroxisomes also house the enzymes for the β-oxidation of fatty acids, purine and amino acid catabolism, methanol oxidation, photorespiration, and biosynthesis

Concluding remarks

In this article, we have attempted to summarize recent findings on the dynamics of peroxisome assembly, proliferation and function and to provide suggestions for future research in these areas. A crucial evaluation of the two models for the multistep process of peroxisome assembly proposed for Y. lipolytica 7., 8. and human fibroblasts 3., 5. will require their testing in other organisms and cell types and would involve the identification and characterization of different peroxisomal subforms

Acknowledgements

We thank our many colleagues too numerous to list for helpful discussion. We also apologize to those colleagues whose work was not cited owing to space limitations. This work was supported by grants MT-9208 and MT-15131 from the Canadian Institutes of Health Research (CIHR) to R.A.R. R.A.R. is a CIHR Senior Scientist and an International Research Scholar of the Howard Hughes Medical Institute.

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Citation Excerpt :
We first noticed that the ACCDGA strains with a PEX10 (peroxisome biogenesis factor 10) knockout developed a smooth surface on agar plates (data not shown), which was similar to the previous online report (iGEM DTU BioBuilders, 2016). Furthermore, the knockout of genes related to peroxisome biogenesis was reported to prevent dimorphic transition in Y. lipolytica (Soon et al., 2019; Thevenieau et al., 2007; Titorenko et al., 1997; Titorenko and Rachubinski, 2001), suggesting that the morphology of the PEX10 knockout strain was predominantly in the yeast form. We further confirmed this by culturing the PEX10 knockout strain in minimal media containing N-acetylglucosamine (YNB-GlucNac10), a well-known hyphae inducer (Perez-Campo and Dominguez, 2001), and the cells were able to retain their yeast forms (Supplementary Fig. 6b).
Acid whey, a byproduct in cheese and yogurt production, demands high costs in disposal at large quantities. Nonetheless, it contains abundant sugars and nutrients that can potentially be utilized by microorganisms. Here we report a novel platform technology that converts acid whey into value-added products using Yarrowia lipolytica. Since wild type strains do not assimilate lactose, a major carbon source in whey, a secreted β-galactosidase was introduced. Additionally, to accelerate galactose metabolism, we overexpressed the relevant native four genes of the Leloir pathway. The engineered strain could achieve rapid total conversion of all carbon sources in acid whey, producing 6.61 g/L of fatty acids (FAs) with a yield of 0.146 g-FAs/g-substrates. Further engineering to introduce an omega-3 desaturase enabled the synthesis of α-linolenic acid from acid whey, producing 10.5 mg/gDCW within a short fermentation time. Finally, PEX10 knockout in our platform strain was shown to minimize hyphal formation in concentrated acid whey cultures, greatly improving fatty acid content. These results demonstrate the feasibility of using acid whey as a previously untapped resource for biotechnology.
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In addition, the intra-ER targeting signal is evolutionarily conserved as human or Drosophila Pex3 signals could functionally replace the yeast signal. However, such intra-ER sorting signals, which remain to be discovered in other PMPs, might direct different PMPs into distinct pER domains that will exit the ER in distinct ppVs [68,106]. Interestingly, other studies highlight the role of the transmembrane domain of secretory proteins as an important determinant for intra-ER sorting and exit through ER exit sites (ERES) [107,108].
Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent discovery, several studies have highlighted key mechanistic details of the pathway. The endoplasmic reticulum (ER) is the primary source of lipids and proteins for the newly-formed peroxisomes. More recently, an intricate sorting process functioning at the ER has been proposed, that segregates specific PMPs first to peroxisome-specific ER domains (pER) and then assembles PMPs selectively into distinct pre-peroxisomal vesicles (ppVs) that later fuse to form import-competent peroxisomes. In addition, plausible roles of the three key peroxins Pex3, Pex16 and Pex19, which are also central to the growth and division pathway, have been suggested in the de novo process. In this review, we discuss key developments and highlight the unexplored avenues in de novo peroxisome biogenesis. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann.
No peroxisome is an island - Peroxisome contact sites
2016, Biochimica et Biophysica Acta - Molecular Cell Research
In order to optimize their multiple cellular functions, peroxisomes must collaborate and communicate with the surrounding organelles. A common way of communication between organelles is through physical membrane contact sites where membranes of two organelles are tethered, facilitating exchange of small molecules and intracellular signaling. In addition contact sites are important for controlling processes such as metabolism, organelle trafficking, inheritance and division. How peroxisomes rely on contact sites for their various cellular activities is only recently starting to be appreciated and explored and the extent of peroxisomal communication, their contact sites and their functions are less characterized. In this review we summarize the identified peroxisomal contact sites, their tethering complexes and their potential physiological roles. Additionally, we highlight some of the preliminary evidence that exists in the field for unexplored peroxisomal contact sites.
This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann.
Multiple paths to peroxisomes: Mechanism of peroxisome maintenance in mammals
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Citation Excerpt :
Although our knowledge about peroxisome biogenesis has evolved and seen some significant advancement over the last few decades, several major questions still remain to be addressed in the near future. For instance, although PMPs can target to peroxisomes via two distinct pathways (direct and indirect) [75,76], the extent that each pathway contributes to the maintenance of peroxisomes in cycling cells is not clear. It is likely that the pathway by which the PMP targets to peroxisomes may depend on the specific PMP, cell type, and environmental stimuli.
Peroxisomes are dynamic organelles that can adjust their size and number in response to cellular demand and environmental stimuli. They can propagate from pre-existing peroxisomes through growth and division, as well as de novo from the endoplasmic reticulum (ER). However, to what extend that these two distinct peroxisome biogenesis pathways are involved in maintaining peroxisome numbers in cycling cells is unclear. Recent studies in yeast suggest that the ER plays a direct role in the maintenance of peroxisomes. However, the role of the ER in mammalian system is under debate. In this review, we outline the recent progress in understanding the biogenesis of mammalian peroxisomes. We herein discuss some of the discrepancies in the literature and the outstanding questions in the field. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann.
Peripheral nervous system defects in a mouse model for peroxisomal biogenesis disorders
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Peroxisome biogenesis disorders (PBD) are autosomal recessive disorders in humans characterized by skeletal, eye and brain abnormalities. Despite the fact that neurological deficits, including peripheral nervous system (PNS) defects, can be observed at birth in some PBD patients including those with PEX10 mutations, the embryological basis of the PNS defects is unclear. Using a forward genetic screen, we identified a mouse model for Pex10 deficiency that exhibits neurological abnormalities during fetal development. Homozygous Pex10 mutant mouse embryos display biochemical abnormalities related to a PBD deficiency. During late embryogenesis, Pex10 homozygous mutant mice experience progressive loss of movement and at birth they become cyanotic and die shortly thereafter. Homozygous Pex10 mutant fetuses display decreased integrity of axons and synapses, over-extension of axons in the diaphragm and decreased Schwann cell numbers. Our neuropathological, molecular and electrophysiological studies provide new insights into the embryological basis of the PNS deficits in a PBD model. Our findings identify PEX10 function, and likely other PEX proteins, as an essential component of the spinal locomotor circuit.
Fission and proliferation of peroxisomes
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Peroxisomes are remarkably dynamic, multifunctional organelles, which react to physiological changes in their cellular environment and adopt their morphology, number, enzyme content and metabolic functions accordingly. At the organelle level, the key molecular machinery controlling peroxisomal membrane elongation and remodeling as well as membrane fission is becoming increasingly established and defined. Key players in peroxisome division are conserved in animals, plants and fungi, and key fission components are shared with mitochondria. However, the physiological stimuli and corresponding signal transduction pathways regulating and modulating peroxisome maintenance and proliferation are, despite a few exceptions, largely unexplored. There is emerging evidence that peroxisomal dynamics and proper regulation of peroxisome number and morphology are crucial for the physiology of the cell, as well as for the pathology of the organism. Here, we discuss several key aspects of peroxisomal fission and proliferation and highlight their association with certain diseases. We address signaling and transcriptional events resulting in peroxisome proliferation, and focus on novel findings concerning the key division components and their interplay. Finally, we present an updated model of peroxisomal growth and division. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.

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Trends in Cell Biology

OpinionDynamics of peroxisome assembly and function

Abstract

Section snippets

Peroxisomes assemble by a multistep pathway

Mechanism of peroxisome fusion

Selective protein import by different peroxisomal subforms

Replenishing early intermediates of the peroxisome assembly pathway

A link between peroxisomes and specific developmental programs

Concluding remarks

Acknowledgements

Trends Genet.

J. Biol. Chem.

FEBS Lett.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Trends Cell Biol.

J. Biol. Chem.

Cell

Cell

Biochim. Biophys. Acta

FEMS Microbiol. Rev.

FEBS Lett.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Trends Biochem. Sci.

FEBS Lett.

Trends Plant Sci.

Trends Cell Biol.

Cell

Molecular Cell Biology

Biogenesis of peroxisomes

Annu. Rev. Cell Biol.

Peroxisome synthesis in the absence of preexisting peroxisomes

J. Cell Biol.

Inhibitors of COPI and COPII do not block PEX3-mediated peroxisome synthesis

J. Cell Biol.

Fusion of small peroxisomal vesicles in vitro reconstructs an early step in the in vivo multistep peroxisome assembly pathway of Yarrowia lipolytica

J. Cell Biol.

Peroxisomal membrane fusion requires two AAA family ATPases, Pex1p and Pex6p

J. Cell Biol.

Biogenesis of peroxisomes: isolation and characterization of two distinct peroxisomal populations from normal and regenerating rat liver

J. Cell Biol.

Peroxisome biogenesis in the yeast Hansenula polymorpha: a structural and functional analysis

Ann. New York Acad. Sci.

Two AAA family peroxins, PpPex1p and PpPex6p, interact with each other in an ATP-dependent manner and are associated with different subcellular membranous structures distinct from peroxisomes

Mol. Cell. Biol.

Metabolic control of peroxisome abundance

J. Cell Sci.

Opinion
Dynamics of peroxisome assembly and function