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Peroxisomes under the Spotlight: Collaboration is the Way to Go

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 61758

Special Issue Editor

Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, 3000 Leuven, Belgium
Interests: molecular biology, biochemistry, and function of peroxisomes; peroxisomal disorders; inter-organelle crosstalk; mitochondria; oxidative stress; redox signaling; monitoring and modulation of the intracellular redox state at the subcellular level; intracellular protein trafficking; pulse labeling of proteins; protein–protein interactions

Special Issue Information

Dear Colleagues,

In 2019, it will be 65 years since the Swedish doctoral student Johannes Rhodin described, for the first time, the existence of special organelles, currently known as peroxisomes, in mouse kidney cells. After being overlooked for a long time, this organelle has now moved into the spotlight of cell biology, biomedical research, and biotechnology. Peroxisomes are remarkably dynamic organelles whose functions can differ substantially across different species, life stages, and environmental conditions. To maintain their function and dynamics, these organelles must exchange substrates, metabolites, and signaling molecules with other subcellular compartments. This is thought to occur via vesicular traffic, membrane contact sites, and membrane transport proteins. Dysregulation of any of these processes has been demonstrated to impact organismal fitness and survival.

This Special Issue aims to provide a forum for researchers around the world to share their latest findings and views on how peroxisomes communicate with their environment to support cellular functions. Potential topics include, but are not limited to, the molecular, biochemical, and cellular mechanisms that control peroxisome dynamics and functions in various organisms and disease states. Both original research articles and review papers that stimulate discussion are welcome.

Prof. Dr. Marc Fransen
Guest Editor

Manuscript Submission Information

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Keywords

  • peroxisome
  • organelle communication
  • contact site
  • membrane transporter
  • signaling messenger
  • lipid metabolism
  • redox metabolism
  • organelle dysfunction

Published Papers (11 papers)

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Research

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10 pages, 887 KiB  
Communication
The Peroxisomal PTS1-Import Defect of PEX1- Deficient Cells Is Independent of Pexophagy in Saccharomyces cerevisiae
by Thomas Mastalski, Rebecca Brinkmeier and Harald W. Platta
Int. J. Mol. Sci. 2020, 21(3), 867; https://doi.org/10.3390/ijms21030867 - 29 Jan 2020
Cited by 5 | Viewed by 2864
Abstract
The important physiologic role of peroxisomes is shown by the occurrence of peroxisomal biogenesis disorders (PBDs) in humans. This spectrum of autosomal recessive metabolic disorders is characterized by defective peroxisome assembly and impaired peroxisomal functions. PBDs are caused by mutations in the peroxisomal [...] Read more.
The important physiologic role of peroxisomes is shown by the occurrence of peroxisomal biogenesis disorders (PBDs) in humans. This spectrum of autosomal recessive metabolic disorders is characterized by defective peroxisome assembly and impaired peroxisomal functions. PBDs are caused by mutations in the peroxisomal biogenesis factors, which are required for the correct compartmentalization of peroxisomal matrix enzymes. Recent work from patient cells that contain the Pex1(G843D) point mutant suggested that the inhibition of the lysosome, and therefore the block of pexophagy, was beneficial for peroxisomal function. The resulting working model proposed that Pex1 may not be essential for matrix protein import at all, but rather for the prevention of pexophagy. Thus, the observed matrix protein import defect would not be caused by a lack of Pex1 activity, but rather by enhanced removal of peroxisomal membranes via pexophagy. In the present study, we can show that the specific block of PEX1 deletion-induced pexophagy does not restore peroxisomal matrix protein import or the peroxisomal function in beta-oxidation in yeast. Therefore, we conclude that Pex1 is directly and essentially involved in peroxisomal matrix protein import, and that the PEX1 deletion-induced pexophagy is not responsible for the defect in peroxisomal function. In order to point out the conserved mechanism, we discuss our findings in the context of the working models of peroxisomal biogenesis and pexophagy in yeasts and mammals. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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22 pages, 4041 KiB  
Article
Rare Human Missense Variants can affect the Function of Disease-Relevant Proteins by Loss and Gain of Peroxisomal Targeting Motifs
by Cheng-Shoong Chong, Markus Kunze, Bernhard Hochreiter, Martin Krenn, Johannes Berger and Sebastian Maurer-Stroh
Int. J. Mol. Sci. 2019, 20(18), 4609; https://doi.org/10.3390/ijms20184609 - 17 Sep 2019
Cited by 6 | Viewed by 3677
Abstract
Single nucleotide variants (SNVs) resulting in amino acid substitutions (i.e., missense variants) can affect protein localization by changing or creating new targeting signals. Here, we studied the potential of naturally occurring SNVs from the Genome Aggregation Database (gnomAD) to result in the loss [...] Read more.
Single nucleotide variants (SNVs) resulting in amino acid substitutions (i.e., missense variants) can affect protein localization by changing or creating new targeting signals. Here, we studied the potential of naturally occurring SNVs from the Genome Aggregation Database (gnomAD) to result in the loss of an existing peroxisomal targeting signal 1 (PTS1) or gain of a novel PTS1 leading to mistargeting of cytosolic proteins to peroxisomes. Filtering down from 32,985 SNVs resulting in missense mutations within the C-terminal tripeptide of 23,064 human proteins, based on gene annotation data and computational prediction, we selected six SNVs for experimental testing of loss of function (LoF) of the PTS1 motif and five SNVs in cytosolic proteins for gain in PTS1-mediated peroxisome import (GoF). Experimental verification by immunofluorescence microscopy for subcellular localization and FRET affinity measurements for interaction with the receptor PEX5 demonstrated that five of the six predicted LoF SNVs resulted in loss of the PTS1 motif while three of five predicted GoF SNVs resulted in de novo PTS1 generation. Overall, we showed that a complementary approach incorporating bioinformatics methods and experimental testing was successful in identifying SNVs capable of altering peroxisome protein import, which may have implications in human disease. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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17 pages, 3602 KiB  
Article
Peroxisome Maintenance Depends on De Novo Peroxisome Formation in Yeast Mutants Defective in Peroxisome Fission and Inheritance
by Justyna P. Wróblewska and Ida J. van der Klei
Int. J. Mol. Sci. 2019, 20(16), 4023; https://doi.org/10.3390/ijms20164023 - 17 Aug 2019
Cited by 5 | Viewed by 3248
Abstract
There is an ongoing debate on how peroxisomes form: by growth and fission of pre-existing peroxisomes or de novo from another membrane. It has been proposed that, in wild type yeast cells, peroxisome fission and careful segregation of the organelles over mother cells [...] Read more.
There is an ongoing debate on how peroxisomes form: by growth and fission of pre-existing peroxisomes or de novo from another membrane. It has been proposed that, in wild type yeast cells, peroxisome fission and careful segregation of the organelles over mother cells and buds is essential for organelle maintenance. Using live cell imaging we observed that cells of the yeast Hansenula polymorpha, lacking the peroxisome fission protein Pex11, still show peroxisome fission and inheritance. Also, in cells of mutants without the peroxisome inheritance protein Inp2 peroxisome segregation can still occur. In contrast, peroxisome fission and inheritance were not observed in cells of a pex11 inp2 double deletion strain. In buds of cells of this double mutant, new organelles likely appear de novo. Growth of pex11 inp2 cells on methanol, a growth substrate that requires functional peroxisomes, is retarded relative to the wild type control. Based on these observations we conclude that in H. polymorpha de novo peroxisome formation is a rescue mechanism, which is less efficient than organelle fission and inheritance to maintain functional peroxisomes. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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17 pages, 2747 KiB  
Article
Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders
by Fabian Dorninger, Anna Gundacker, Gerhard Zeitler, Daniela D. Pollak and Johannes Berger
Int. J. Mol. Sci. 2019, 20(16), 3929; https://doi.org/10.3390/ijms20163929 - 13 Aug 2019
Cited by 25 | Viewed by 4818
Abstract
Ether lipids form a specialized subgroup of phospholipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a [...] Read more.
Ether lipids form a specialized subgroup of phospholipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a mouse model. Here, we focused on a more detailed examination of the behavioral phenotype of ether lipid-deficient mice (Gnpat KO) and describe a set of features related to human psychiatric disorders. Gnpat KO mice show strongly impaired social interaction as well as nestlet shredding and marble burying, indicating disturbed execution of inborn behavioral patterns. Also, compromised contextual and cued fear conditioning in these animals suggests a considerable memory deficit, thus potentially forming a connection to the previously determined ether lipid deficit in human patients with Alzheimer’s disease. Nesting behavior and the preference for social novelty proved normal in ether lipid-deficient mice. In addition, we detected task-specific alterations in paradigms assessing depression- and anxiety-related behavior. The reported behavioral changes may be used as easy readout for the success of novel treatment strategies against ether lipid deficiency in ameliorating nervous system-associated symptoms. Furthermore, our findings underline that ether lipids are paramount for brain function and demonstrate their relevance for cognitive, social, and emotional behavior. We hereby substantially extend previous observations suggesting a link between deficiency in ether lipids and human mental illnesses, particularly autism and attention-deficit hyperactivity disorder. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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Review

Jump to: Research

27 pages, 2093 KiB  
Review
Pexophagy: A Model for Selective Autophagy
by Kyla Germain and Peter K. Kim
Int. J. Mol. Sci. 2020, 21(2), 578; https://doi.org/10.3390/ijms21020578 - 16 Jan 2020
Cited by 63 | Viewed by 8495
Abstract
The removal of damaged or superfluous organelles from the cytosol by selective autophagy is required to maintain organelle function, quality control and overall cellular homeostasis. Precisely how substrate selectivity is achieved, and how individual substrates are degraded during selective autophagy in response to [...] Read more.
The removal of damaged or superfluous organelles from the cytosol by selective autophagy is required to maintain organelle function, quality control and overall cellular homeostasis. Precisely how substrate selectivity is achieved, and how individual substrates are degraded during selective autophagy in response to both extracellular and intracellular cues is not well understood. The aim of this review is to highlight pexophagy, the autophagic degradation of peroxisomes, as a model for selective autophagy. Peroxisomes are dynamic organelles whose abundance is rapidly modulated in response to metabolic demands. Peroxisomes are routinely turned over by pexophagy for organelle quality control yet can also be degraded by pexophagy in response to external stimuli such as amino acid starvation or hypoxia. This review discusses the molecular machinery and regulatory mechanisms governing substrate selectivity during both quality-control pexophagy and pexophagy in response to external stimuli, in yeast and mammalian systems. We draw lessons from pexophagy to infer how the cell may coordinate the degradation of individual substrates by selective autophagy across different cellular cues. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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17 pages, 6786 KiB  
Review
A Mechanistic Perspective on PEX1 and PEX6, Two AAA+ Proteins of the Peroxisomal Protein Import Machinery
by Ana G. Pedrosa, Tânia Francisco, Maria J. Ferreira, Tony A. Rodrigues, Aurora Barros-Barbosa and Jorge E. Azevedo
Int. J. Mol. Sci. 2019, 20(21), 5246; https://doi.org/10.3390/ijms20215246 - 23 Oct 2019
Cited by 7 | Viewed by 4988
Abstract
In contrast to many protein translocases that use ATP or GTP hydrolysis as the driving force to transport proteins across biological membranes, the peroxisomal matrix protein import machinery relies on a regulated self-assembly mechanism for this purpose and uses ATP hydrolysis only to [...] Read more.
In contrast to many protein translocases that use ATP or GTP hydrolysis as the driving force to transport proteins across biological membranes, the peroxisomal matrix protein import machinery relies on a regulated self-assembly mechanism for this purpose and uses ATP hydrolysis only to reset its components. The ATP-dependent protein complex in charge of resetting this machinery—the Receptor Export Module (REM)—comprises two members of the “ATPases Associated with diverse cellular Activities” (AAA+) family, PEX1 and PEX6, and a membrane protein that anchors the ATPases to the organelle membrane. In recent years, a large amount of data on the structure/function of the REM complex has become available. Here, we discuss the main findings and their mechanistic implications. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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22 pages, 1021 KiB  
Review
Multilevel Regulation of Peroxisomal Proteome by Post-Translational Modifications
by Luisa M. Sandalio, Cecilia Gotor, Luis C. Romero and Maria C. Romero-Puertas
Int. J. Mol. Sci. 2019, 20(19), 4881; https://doi.org/10.3390/ijms20194881 - 01 Oct 2019
Cited by 34 | Viewed by 4871
Abstract
Peroxisomes, which are ubiquitous organelles in all eukaryotes, are highly dynamic organelles that are essential for development and stress responses. Plant peroxisomes are involved in major metabolic pathways, such as fatty acid β-oxidation, photorespiration, ureide and polyamine metabolism, in the biosynthesis of jasmonic, [...] Read more.
Peroxisomes, which are ubiquitous organelles in all eukaryotes, are highly dynamic organelles that are essential for development and stress responses. Plant peroxisomes are involved in major metabolic pathways, such as fatty acid β-oxidation, photorespiration, ureide and polyamine metabolism, in the biosynthesis of jasmonic, indolacetic, and salicylic acid hormones, as well as in signaling molecules such as reactive oxygen and nitrogen species (ROS/RNS). Peroxisomes are involved in the perception of environmental changes, which is a complex process involving the regulation of gene expression and protein functionality by protein post-translational modifications (PTMs). Although there has been a growing interest in individual PTMs in peroxisomes over the last ten years, their role and cross-talk in the whole peroxisomal proteome remain unclear. This review provides up-to-date information on the function and crosstalk of the main peroxisomal PTMs. Analysis of whole peroxisomal proteomes shows that a very large number of peroxisomal proteins are targeted by multiple PTMs, which affect redox balance, photorespiration, the glyoxylate cycle, and lipid metabolism. This multilevel PTM regulation could boost the plasticity of peroxisomes and their capacity to regulate metabolism in response to environmental changes. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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29 pages, 2568 KiB  
Review
Peroxisomes in Immune Response and Inflammation
by Francesca Di Cara, Pierre Andreoletti, Doriane Trompier, Anne Vejux, Margret H. Bülow, Julia Sellin, Gérard Lizard, Mustapha Cherkaoui-Malki and Stéphane Savary
Int. J. Mol. Sci. 2019, 20(16), 3877; https://doi.org/10.3390/ijms20163877 - 08 Aug 2019
Cited by 73 | Viewed by 9634
Abstract
The immune response is essential to protect organisms from infection and an altered self. An organism’s overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic [...] Read more.
The immune response is essential to protect organisms from infection and an altered self. An organism’s overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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10 pages, 853 KiB  
Review
Peroxisomes and Innate Immunity: Antiviral Response and Beyond
by Ana Rita Ferreira, Mariana Marques and Daniela Ribeiro
Int. J. Mol. Sci. 2019, 20(15), 3795; https://doi.org/10.3390/ijms20153795 - 03 Aug 2019
Cited by 32 | Viewed by 5136
Abstract
Peroxisomes are ubiquitous organelles with well-defined functions in lipid and reactive oxygen species metabolism, having a significant impact on a large number of important diseases. Growing evidence points to them, in concert with mitochondria, as important players within the antiviral response. In this [...] Read more.
Peroxisomes are ubiquitous organelles with well-defined functions in lipid and reactive oxygen species metabolism, having a significant impact on a large number of important diseases. Growing evidence points to them, in concert with mitochondria, as important players within the antiviral response. In this review we summarize and discuss the recent findings concerning the relevance of peroxisomes within innate immunity. We not only emphasize their importance as platforms for cellular antiviral signaling but also review the current information concerning their role in the control of bacterial infections. We furthermore review the recent data that pinpoints peroxisomes as regulators of inflammatory processes. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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25 pages, 3648 KiB  
Review
Structural Mapping of Missense Mutations in the Pex1/Pex6 Complex
by Anne Schieferdecker and Petra Wendler
Int. J. Mol. Sci. 2019, 20(15), 3756; https://doi.org/10.3390/ijms20153756 - 01 Aug 2019
Cited by 12 | Viewed by 4003
Abstract
Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. [...] Read more.
Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast scPex1/scPex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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20 pages, 1453 KiB  
Review
Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease
by Celien Lismont, Iulia Revenco and Marc Fransen
Int. J. Mol. Sci. 2019, 20(15), 3673; https://doi.org/10.3390/ijms20153673 - 26 Jul 2019
Cited by 106 | Viewed by 9162
Abstract
Hydrogen peroxide (H2O2), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or [...] Read more.
Hydrogen peroxide (H2O2), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipid metabolism, also serve as hubs in the H2O2 signaling network. We first briefly introduce the basic concepts of how H2O2 can drive cellular signaling events. Next, we outline the peroxisomal enzyme systems involved in H2O2 metabolism in mammals and reflect on how this oxidant can permeate across the organellar membrane. In addition, we provide an up-to-date overview of molecular targets and biological processes that can be affected by changes in peroxisomal H2O2 metabolism. Where possible, emphasis is placed on the molecular mechanisms and factors involved. From the data presented, it is clear that there are still numerous gaps in our knowledge. Therefore, gaining more insight into how peroxisomes are integrated in the cellular H2O2 signaling network is of key importance to unravel the precise role of peroxisomal H2O2 production and scavenging in normal and pathological conditions. Full article
(This article belongs to the Special Issue Peroxisomes under the Spotlight: Collaboration is the Way to Go)
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