Editorial: Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

This is the final version of the article. Available from Frontiers Media via the DOI in this recordSupported by BBSRC (BB/K006231/1, BB/N01541X/1) and FP-7-PEOPLE-2012-Marie Curie-ITN 316723 PERFUME

Organelle Interplay - Peroxisome Interactions in Health and Disease

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Peroxisomes are multifunctional, dynamic, membrane‐bound organelles with important functions in cellular lipid metabolism, rendering them essential for human health and development. Important roles for peroxisomes in signaling and the fine‐tuning of cellular processes are emerging, which integrate them in a complex network of interacting cellular compartments. Like many other organelles, peroxisomes communicate through membrane contact sites. For example, peroxisomal growth, positioning, and lipid metabolism involves contacts with the endoplasmic reticulum (ER). Here, we discuss the most recent findings on peroxisome‐organelle interactions including peroxisome‐ER interplay at membrane contacts sites, and functional interplay with mitochondria, lysosomes, and lipid droplets in mammalian cells. We address tether proteins, metabolic cooperation, and the impact of peroxisome interactions on human health and disease.Biotechnology & Biological Sciences Research Council (BBSRC)Medical Research Council (MRC)University of ExeterGerman Research FoundationUniversity of Heidelber

Detection and immunolabelling of peroxisomal proteins

This is the author accepted manuscript. The final version is available from Humana Press via the DOI in this record.Peroxisomes are essential organelles in mammals which contribute to cellular lipid metabolism and redox homeostasis. The spectrum of their functions in human health and disease is far from being complete, and unexpected and novel roles of peroxisomes are being discovered. To date, those include novel biological roles in anti-viral defence, as intracellular signalling platforms and as protective organelles in sensory cells. Furthermore, peroxisomes are part of a complex network of interacting subcellular compartments which involves metabolic cooperation, cross-talk and membrane contacts. As potentially novel peroxisomal proteins are continuously discovered, there is great interest in the verification of their peroxisomal localisation. Here, we present protocols used successfully in our laboratory for the detection and immunolabelling of peroxisomal proteins in cultured mammalian cells. We present immunofluorescence and fluorescence-based techniques as well as reagents to determine peroxisome-specific targeting and localisation of candidate proteins.We would like to thank A. Manner for providing images for Fig. 1D. This work was supported by the Marie Curie Initial Training Network (ITN) action (FP7-2012-PERFUME-316723) and the Biotechnology and Biological Sciences Research Council (BB/K006231/1; BB/N01541X/1)

The peroxisome: an update on mysteries 2.0

This is the final version of the article. Available from Springer Verlag via the DOI in this record.Peroxisomes are key metabolic organelles, which contribute to cellular lipid metabolism, e.g. the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as cellular redox balance. Peroxisomal dysfunction has been linked to severe metabolic disorders in man, but peroxisomes are now also recognised as protective organelles with a wider significance in human health and potential impact on a large number of globally important human diseases such as neurodegeneration, obesity, cancer, and age-related disorders. Therefore, the interest in peroxisomes and their physiological functions has significantly increased in recent years. In this review, we intend to highlight recent discoveries, advancements and trends in peroxisome research, and present an update as well as a continuation of two former review articles addressing the unsolved mysteries of this astonishing organelle. We summarise novel findings on the biological functions of peroxisomes, their biogenesis, formation, membrane dynamics and division, as well as on peroxisome-organelle contacts and cooperation. Furthermore, novel peroxisomal proteins and machineries at the peroxisomal membrane are discussed. Finally, we address recent findings on the role of peroxisomes in the brain, in neurological disorders, and in the development of cancer.This work was supported by the Biotechnology and Biological Sciences Research Council (BB/K006231/1, BB/N01541X/1) and MRC CiC 08135, University of Exeter (to M.S.). M.I. is supported by the German Research Foundation (DFG grant 397476530) and MEAMEDMA Anschubförderung, Medical Faculty Mannheim, University of Heidelberg

Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this record.Cooperation between cellular organelles such as mitochondria, peroxisomes and the ER is essential for a variety of important and diverse metabolic processes. Effective communication and metabolite exchange requires physical linkages between the organelles, predominantly in the form of organelle contact sites. At such contact sites organelle membranes are brought into close proximity by the action of molecular tethers, which often consist of specific protein pairs anchored in the membrane of the opposing organelles. Currently numerous tethering components have been identified which link the ER with multiple other organelles but knowledge of the factors linking the ER with peroxisomes is limited. Peroxisome-ER interplay is important because it is required for the biosynthesis of unsaturated fatty acids, ether-phospholipids and sterols with defects in these functions leading to severe diseases. Here we characterise acyl-CoA binding domain protein 4 (ACBD4) as a tail-anchored peroxisomal membrane protein which interacts with the ER protein, vesicle-associated membrane protein-associated protein–B (VAPB) to promote peroxisome-ER associations.We thank all colleagues who provided plasmids and antibodies, and T Levine for sharing data. This work was supported by BBSRC (BB/K006231/1, BB/N01541X/1). MS is supported by the Marie Curie Initial Training Network action PerFuMe (316723). The authors declare no competing financial interests

The different facets of organelle interplay - an overview of organelle interactions

ReviewThis Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.Membrane-bound organelles such as mitochondria, peroxisomes, or the endoplasmic reticulum (ER) create distinct environments to promote specific cellular tasks such as ATP production, lipid breakdown, or protein export. During recent years, it has become evident that organelles are integrated into cellular networks regulating metabolism, intracellular signaling, cellular maintenance, cell fate decision, and pathogen defence. In order to facilitate such signaling events, specialized membrane regions between apposing organelles bear distinct sets of proteins to enable tethering and exchange of metabolites and signaling molecules. Such membrane associations between the mitochondria and a specialized site of the ER, the mitochondria associated-membrane (MAM), as well as between the ER and the plasma membrane (PAM) have been partially characterized at the molecular level. However, historical and recent observations imply that other organelles like peroxisomes, lysosomes, and lipid droplets might also be involved in the formation of such apposing membrane contact sites. Alternatively, reports on so-called mitochondria derived-vesicles (MDV) suggest alternative mechanisms of organelle interaction. Moreover, maintenance of cellular homeostasis requires the precise removal of aged organelles by autophagy—a process which involves the detection of ubiquitinated organelle proteins by the autophagosome membrane, representing another site of membrane associated-signaling. This review will summarize the available data on the existence and composition of organelle contact sites and the molecular specializations each site uses in order to provide a timely overview on the potential functions of organelle interaction.BBSRCFP-7-PEOPLE-2012-Marie Curie-ITN 316723 PERFUMEPortuguese Foundation for Science and Technology (FCT

Fission Impossible (?) – New Insights into Disorders of Peroxisome Dynamics

This is the author accepted manuscript.Data Availability Statement: All datasets generated for this study are included in the article.Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane shaping protein PEX11β and division proteins such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome-ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome-ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussedBiotechnology & Biological Sciences Research Council (BBSRC

Intracellular redistribution of neuronal peroxisomes in response to ACBD5 expression

This is the final version. Available from Public Library of Science via the DOI in this record. Data Availability: All relevant data are within the manuscript and its Supporting Information files.Peroxisomes can be frequently found in proximity to other subcellular organelles such as the endoplasmic reticulum (ER), mitochondria or lysosomes. The tail-anchored protein ACBD5 was recently identified as part of a tethering complex at peroxisome-ER contact sites, interacting with the ER resident protein VAPB. Contact site disruption was found to significantly increase peroxisome motility, apparently interfering with intracellular positioning systems. Unlike other somatic cells, neurons have to distribute organelles across relatively long distances in order to maintain their extraordinary cellular polarity. Using confocal live imaging microscopy in cultured hippocampal neurons we observed that peroxisomes and mitochondria show a strikingly similar motility with approximately 10% performing microtubule-driven long range movements. In order to investigate if ER contacts influence overall peroxisome motility and cellular distribution patterns, hippocampal neurons were transfected with plasmids encoding ACBD5 to stimulate peroxisome-ER interactions. Overexpression of ACBD5 reduced peroxisomal long range movements in the neurites of the hippocampal cells by 70%, implying that ER attachment counteracts microtubule-driven peroxisome transport, while mitochondrial motility was unaffected. Moreover, the analyses of peroxisome distribution in fixed neurons unveiled a significant redistribution of peroxisomes towards the periphery of the perikaryon underneath the plasma membrane and into neurites, where peroxisomes are frequently found in close proximity to mitochondria. Surprisingly, further analysis of peroxisome and VAPB distribution upon ACBD5 expression did not reveal a substantial colocalization, implying this effect may be independent of VAPB. In line with these findings, expression of an ACBD5 variant unable to bind to VAPB still altered the localization of peroxisomes in the same way as the wild-type ACBD5. Thus, we conclude, that the VAPB-ACBD5 facilitated peroxisome-ER interaction is not responsible for the observed organelle redistribution in neurons. Rather, we suggest that additional ACBD5-binding proteins in neurons may tether peroxisomes to contact sites at or near the plasma membrane of neurons.Deutsche Forschungsgemeinschaft DFGMEAMEDMA Anschubförderung of the University of HeidelbergBiotechnology & Biological Sciences Research Council (BBSRC)Wellcome Trus

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation - Volume II

Eukaryotic cells contain distinct membrane-bound organelles, which compartmentalize cellular proteins to fulfil a variety of vital functions. In contrast to being isolated and static entities (e.g., peroxisomes, mitochondria, lipid droplets), organelles rather display dynamic changes, interact with each other, share certain proteins and show metabolic cooperation and cross talk. Despite great advances in the identification and characterization of essential components and molecular mechanisms associated with the biogenesis and function of organelles, investigating how organelles interact and are incorporated into metabolic pathways and signaling networks has become a novel focus in the field of cellular biology. Organelle cooperation requires sophisticated targeting systems, which regulate the proper distribution of shared proteins to more than one organelle. Organelle motility and membrane remodeling support organelle interaction and contact. This contact can be mediated by membrane proteins residing on different organelles, which can serve as molecular tethers to physically link opposing membranes. They can also contribute to the exchange of metabolites and ions, or act in the assembly of signaling platforms. In this regard, organelle communication events have been associated with important cellular functions such as apoptosis, antiviral defense, organelle division/biogenesis, ROS metabolism and signaling, and various metabolic pathways such as synthesis and breakdown of lipids including cholesterol. In this Research Topic, we will focus on recent novel findings on the underlying molecular mechanisms and physiological significance of organelle interaction and cooperation with a particular focus on mitochondria, peroxisomes, endoplasmic reticulum, lysosomes and lipid droplets and their impact on the regulation of cellular homeostasis. Our understanding of how organelles physically interact and use cellular signaling systems to coordinate functional networks between each other is still far from being fully understood. Nevertheless, recent discoveries of defined membrane structures such as the mitochondria-ER associated membranes (MAM) are revealing how membrane domains enriched in specific proteins transmit signals across organelle boundaries, allowing one organelle to influence the function of another. In addition to its role as a mediator between mitochondria and the ER, contacts between the MAM and peroxisomes contribute to antiviral signaling, and specialized regions of the ER are supposed to initiate peroxisome biogenesis, whereas membrane contacts between peroxisomes, lipid droplets, lysosomes and the ER mediate lipid metabolism. A number of tethering complexes facilitating such contacts have been identified in recent years and more will likely follow in the near future. Additionally, the first human genetic disorders with mutations in tethering proteins have been reported. Despite these findings, the functional significance of most contact sites is still far from being understood and knowledge about the regulation of their formation and detachment is still scarce. Identifying the key molecular players of such specialized membrane structures is a prerequisite to understand how organelle communication is physically accomplished and will lead to the identification of new regulatory networks. Cytosolic messenger systems (e.g., kinase/phosphatase systems or redox signaling) may contribute to the general coordination of organelle communication but may also have a direct impact on the formation of tethering complexes. This Research Topic will integrate new findings from both modes of communication and will provide new perspectives for the functional significance of cross talk among organelles

Editorial: “Molecular mechanisms and physiological significance of organelle interactions and cooperation—Volume II”

This is the final version. Available from Frontiers Media via the DOI in this record. Biotechnology & Biological Sciences Research Council (BBSRC)Biotechnology & Biological Sciences Research Council (BBSRC)Biotechnology & Biological Sciences Research Council (BBSRC)UKR