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Advances in Experimental Medicine and... 2020Peroxisome is an organelle conserved in almost all eukaryotic cells with a variety of functions in cellular metabolism, including fatty acid β-oxidation, synthesis of... (Review)
Review
Peroxisome is an organelle conserved in almost all eukaryotic cells with a variety of functions in cellular metabolism, including fatty acid β-oxidation, synthesis of ether glycerolipid plasmalogens, and redox homeostasis. Such metabolic functions and the exclusive importance of peroxisomes have been highlighted in fatal human genetic disease called peroxisomal biogenesis disorders (PBDs). Recent advances in this field have identified over 30 PEX genes encoding peroxins as essential factors for peroxisome biogenesis in various species from yeast to humans. Functional delineation of the peroxins has revealed that peroxisome biogenesis comprises the processes, involving peroxisomal membrane assembly, matrix protein import, division, and proliferation. Catalase, the most abundant peroxisomal enzyme, catalyzes decomposition of hydrogen peroxide. Peroxisome plays pivotal roles in the cellular redox homeostasis and the response to oxidative stresses, depending on intracellular localization of catalase.
Topics: Humans; Intracellular Membranes; Metabolic Networks and Pathways; Oxidation-Reduction; Oxidative Stress; Peroxisomal Disorders; Peroxisomes; Protein Transport
PubMed: 33417203
DOI: 10.1007/978-3-030-60204-8_1 -
Trends in Cell Biology Jan 2023Peroxisomes are essential metabolic organelles, well known for their roles in the metabolism of complex lipids and reactive ionic species. In the past 10 years,... (Review)
Review
Peroxisomes are essential metabolic organelles, well known for their roles in the metabolism of complex lipids and reactive ionic species. In the past 10 years, peroxisomes have also been cast as central regulators of immunity. Lipid metabolites of peroxisomes, such as polyunsaturated fatty acids (PUFAs), are precursors for important immune mediators, including leukotrienes (LTs) and resolvins. Peroxisomal redox metabolism modulates cellular immune signaling such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Additionally, peroxisomal β-oxidation and ether lipid synthesis control the development and aspects of the activation of both innate and adaptive immune cells. Finally, peroxisome number and metabolic activity have been linked to inflammatory diseases. These discoveries have opened avenues of investigation aimed at targeting peroxisomes for therapeutic intervention in immune disorders, inflammation, and cancer.
Topics: Humans; Peroxisomes; Fatty Acids; Oxidation-Reduction; Neoplasms; Inflammation
PubMed: 35788297
DOI: 10.1016/j.tcb.2022.06.001 -
Cells Jul 2020Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redoxbalance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid... (Review)
Review
Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redoxbalance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid synthesis, bile acidsynthesis, and reactive oxygen species homeostasis. Human disorders caused by genetic mutations inperoxisome genes have led to extensive studies on peroxisome biology. Peroxisomal defects are linkedto metabolic dysregulation in diverse human diseases, such as neurodegeneration and age-relateddisorders, revealing the significance of peroxisome metabolism in human health. Cancer is a diseasewith metabolic aberrations. Despite the critical role of peroxisomes in cell metabolism, the functionaleects of peroxisomes in cancer are not as well recognized as those of other metabolic organelles,such as mitochondria. In addition, the significance of peroxisomes in cancer is less appreciated thanit is in degenerative diseases. In this review, I summarize the metabolic pathways in peroxisomesand the dysregulation of peroxisome metabolism in cancer. In addition, I discuss the potential ofinactivating peroxisomes to target cancer metabolism, which may pave the way for more eectivecancer treatment.
Topics: Animals; Biosynthetic Pathways; Homeostasis; Humans; Models, Biological; Neoplasms; Peroxisomes; Reactive Oxygen Species
PubMed: 32674458
DOI: 10.3390/cells9071692 -
Advances in Experimental Medicine and... 2020Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including β-oxidation of fatty acids and synthesis of... (Review)
Review
Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including β-oxidation of fatty acids and synthesis of ether-linked glycerophospholipids, such as plasmalogens. Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs). Fourteen complementation groups of PBDs are found, and their complementing genes termed PEXs are isolated. Several new mutations in peroxins from patients with mild PBD phenotype or patients with phenotypes unrelated to the commonly observed impairments of PBD patients are found by next-generation sequencing. Exploring a dysfunctional step(s) caused by the mutation is important for unveiling the pathogenesis of novel mutation by means of cellular and biochemical analyses.
Topics: Humans; Mutation; Peroxisomal Disorders; Peroxisomes; Phenotype
PubMed: 33417206
DOI: 10.1007/978-3-030-60204-8_4 -
Nature May 2023Peroxisomes are organelles that carry out β-oxidation of fatty acids and amino acids. Both rare and prevalent diseases are caused by their dysfunction. Among...
Peroxisomes are organelles that carry out β-oxidation of fatty acids and amino acids. Both rare and prevalent diseases are caused by their dysfunction. Among disease-causing variant genes are those required for protein transport into peroxisomes. The peroxisomal protein import machinery, which also shares similarities with chloroplasts, is unique in transporting folded and large, up to 10 nm in diameter, protein complexes into peroxisomes. Current models postulate a large pore formed by transmembrane proteins; however, so far, no pore structure has been observed. In the budding yeast Saccharomyces cerevisiae, the minimum transport machinery includes the membrane proteins Pex13 and Pex14 and the cargo-protein-binding transport receptor, Pex5. Here we show that Pex13 undergoes liquid-liquid phase separation (LLPS) with Pex5-cargo. Intrinsically disordered regions in Pex13 and Pex5 resemble those found in nuclear pore complex proteins. Peroxisomal protein import depends on both the number and pattern of aromatic residues in these intrinsically disordered regions, consistent with their roles as 'stickers' in associative polymer models of LLPS. Finally, imaging fluorescence cross-correlation spectroscopy shows that cargo import correlates with transient focusing of GFP-Pex13 and GFP-Pex14 on the peroxisome membrane. Pex13 and Pex14 form foci in distinct time frames, suggesting that they may form channels at different saturating concentrations of Pex5-cargo. Our findings lead us to suggest a model in which LLPS of Pex5-cargo with Pex13 and Pex14 results in transient protein transport channels.
Topics: Intracellular Membranes; Membrane Proteins; Peroxins; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Phase Transition; Protein Binding; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Intrinsically Disordered Proteins
PubMed: 37165185
DOI: 10.1038/s41586-023-06044-1 -
Redox Biology Nov 2023Despite intensive research on peroxisome biochemistry, the role of glutathione in peroxisomal redox homeostasis has remained a matter of speculation for many years, and... (Review)
Review
Despite intensive research on peroxisome biochemistry, the role of glutathione in peroxisomal redox homeostasis has remained a matter of speculation for many years, and only recently has this issue started to be experimentally addressed. Here, we summarize and compare data from several organisms on the peroxisome-glutathione topic. It is clear from this comparison that the repertoire of glutathione-utilizing enzymes in peroxisomes of different organisms varies widely. In addition, the available data suggest that the kinetic connectivity between the cytosolic and peroxisomal pools of glutathione may also be different in different organisms, with some possessing a peroxisomal membrane that is promptly permeable to glutathione whereas in others this may not be the case. However, regardless of the differences, the picture that emerges from all these data is that glutathione is a crucial component of the antioxidative system that operates inside peroxisomes in all organisms.
Topics: Peroxisomes; Glutathione; Antioxidants; Oxidation-Reduction; Homeostasis
PubMed: 37804696
DOI: 10.1016/j.redox.2023.102917 -
Biochimica Et Biophysica Acta.... Nov 2022Peroxisomes are single-membrane organelles essential for cell metabolism including the β-oxidation of fatty acids, synthesis of etherlipid plasmalogens, and redox... (Review)
Review
Peroxisomes are single-membrane organelles essential for cell metabolism including the β-oxidation of fatty acids, synthesis of etherlipid plasmalogens, and redox homeostasis. Investigations into peroxisome biogenesis and the human peroxisome biogenesis disorders (PBDs) have identified 14 PEX genes encoding peroxins involved in peroxisome biogenesis and the mutation of PEX genes is responsible for the PBDs. Many recent findings have further advanced our understanding of the biology, physiology, and consequences of a functional deficit of peroxisomes. In this Review, we discuss cell defense mechanisms that counteract oxidative stress by 1) a proapoptotic Bcl-2 factor BAK-mediated release to the cytosol of HO-degrading catalase from peroxisomes and 2) peroxisomal import suppression of catalase by Ser232-phosphorylation of Pex14, a docking protein for the Pex5-PTS1 complex. With respect to peroxisome division, the important issue of how the energy-rich GTP is produced and supplied for the division process was recently addressed by the discovery of a nucleoside diphosphate kinase-like protein, termed DYNAMO1 in a lower eukaryote, which has a mammalian homologue NME3. In regard to the mechanisms underlying the pathogenesis of PBDs, a new PBD model mouse defective in Pex14 manifests a dysregulated brain-derived neurotrophic factor (BDNF)-TrkB pathway, an important signaling pathway for cerebellar morphogenesis. Communications between peroxisomes and other organelles are also addressed.
Topics: Animals; Catalase; Homeostasis; Humans; Hydrogen Peroxide; Mammals; Mice; Peroxisomal Disorders; Peroxisomes
PubMed: 35917894
DOI: 10.1016/j.bbamcr.2022.119330 -
Sub-cellular Biochemistry 2018As a laboratory animal, Drosophila melanogaster has made extensive contributions to understanding many areas of fundamental biology as well as being an effective model... (Review)
Review
As a laboratory animal, Drosophila melanogaster has made extensive contributions to understanding many areas of fundamental biology as well as being an effective model for human disease. Until recently, there was relatively little known about fly peroxisomes. There were early studies that examined the role of peroxisome enzymes during development of organs like the eye. However, with the advent of a well-annotated, sequenced genome, several groups have collectively determined, first by sequence homology and increasingly by functional studies, Drosophila Peroxins and related peroxisome proteins. Notably, it was shown that Drosophila peroxisome biogenesis is mediated via a well-conserved PTS1 import system. Although the fly genome encodes a Pex7 homologue, a canonical PTS2 import system does not seem to be conserved in Drosophila. Given the homology between Drosophila and Saccharomyces cerevisiae or Homo sapiens peroxisome biogenesis and function, Drosophila has emerged as an effective multicellular system to model human Peroxisome Biogenesis Disorders. Finally, Drosophila peroxisome research has recently come into its own, facilitating new discoveries into the role of peroxisomes within specific tissues, such as testes or immune cells.
Topics: Animals; Disease Models, Animal; Drosophila melanogaster; Humans; Peroxisomal Disorders; Peroxisomes; Saccharomyces cerevisiae
PubMed: 30378026
DOI: 10.1007/978-981-13-2233-4_10 -
Histochemistry and Cell Biology Feb 2024Peroxisomes are highly dynamic, oxidative organelles with key metabolic functions in cellular lipid metabolism, such as the β-oxidation of fatty acids and the synthesis... (Review)
Review
Peroxisomes are highly dynamic, oxidative organelles with key metabolic functions in cellular lipid metabolism, such as the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as the regulation of cellular redox balance. Loss of peroxisomal functions causes severe metabolic disorders in humans. Furthermore, peroxisomes also fulfil protective roles in pathogen and viral defence and immunity, highlighting their wider significance in human health and disease. This has sparked increasing interest in peroxisome biology and their physiological functions. This review presents an update and a continuation of three previous review articles addressing the unsolved mysteries of this remarkable organelle. We continue to highlight recent discoveries, advancements, and trends in peroxisome research, and address novel findings on the metabolic functions of peroxisomes, their biogenesis, protein import, membrane dynamics and division, as well as on peroxisome-organelle membrane contact sites and organelle cooperation. Furthermore, recent insights into peroxisome organisation through super-resolution microscopy are discussed. Finally, we address new roles for peroxisomes in immune and defence mechanisms and in human disorders, and for peroxisomal functions in different cell/tissue types, in particular their contribution to organ-specific pathologies.
Topics: Humans; Peroxisomes; Lipid Metabolism; Oxidation-Reduction
PubMed: 38244103
DOI: 10.1007/s00418-023-02259-5 -
Annual Review of Cell and Developmental... 2001Fifteen years ago, we had a model of peroxisome biogenesis that involved growth and division of preexisting peroxisomes. Today, thanks to genetically tractable model... (Review)
Review
Fifteen years ago, we had a model of peroxisome biogenesis that involved growth and division of preexisting peroxisomes. Today, thanks to genetically tractable model organisms and Chinese hamster ovary cells, 23 PEX genes have been cloned that encode the machinery ("peroxins") required to assemble the organelle. Membrane assembly and maintenance requires three of these (peroxins 3, 16, and 19) and may occur without the import of the matrix (lumen) enzymes. Matrix protein import follows a branched pathway of soluble recycling receptors, with one branch for each class of peroxisome targeting sequence (two are well characterized), and a common trunk for all. At least one of these receptors, Pex5p, enters and exits peroxisomes as it functions. Proliferation of the organelle is regulated by Pex11p. Peroxisome biogenesis is remarkably conserved among eukaryotes. A group of fatal, inherited neuropathologies are recognized as peroxisome biogenesis diseases; the responsible genes are orthologs of yeast or Chinese hamster ovary peroxins. Future studies must address the mechanism by which folded, oligomeric enzymes enter the organelle, how the peroxisome divides, and how it segregates at cell division. Most pex mutants contain largely empty membrane "ghosts" of peroxisomes; a few mutants apparently lacking peroxisomes entirely have led some to propose the de novo formation of the organelle. However, there is evidence for residual peroxisome membrane vesicles ("protoperoxisomes") in some of these, and the preponderance of data supports the continuity of the peroxisome compartment in space and time and between generations of cells.
Topics: Animals; CHO Cells; Cricetinae; Endoplasmic Reticulum; Evolution, Molecular; Humans; Membrane Proteins; Microbodies; Models, Biological; Peroxisomal Disorders; Peroxisomes; Protein Transport; Saccharomyces cerevisiae; Terminology as Topic
PubMed: 11687502
DOI: 10.1146/annurev.cellbio.17.1.701