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Science Advances May 2023Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as...
Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.
Topics: Lipogenesis; Acetyl Coenzyme A; Acetates; ATP Citrate (pro-S)-Lyase; Mitochondria; Homeostasis; Stress, Physiological
PubMed: 37134162
DOI: 10.1126/sciadv.adf0138 -
Frontiers in Physiology 2022Organelles within the cell are highly dynamic entities, requiring dramatic morphological changes to support their function and maintenance. As a result, organelle... (Review)
Review
Organelles within the cell are highly dynamic entities, requiring dramatic morphological changes to support their function and maintenance. As a result, organelle membranes are also highly dynamic, adapting to a range of topologies as the organelle changes shape. In particular, peroxisomes-small, ubiquitous organelles involved in lipid metabolism and reactive oxygen species homeostasis-display a striking plasticity, for example, during the growth and division process by which they proliferate. During this process, the membrane of an existing peroxisome elongates to form a tubule, which then constricts and ultimately undergoes scission to generate new peroxisomes. Dysfunction of this plasticity leads to diseases with developmental and neurological phenotypes, highlighting the importance of peroxisome dynamics for healthy cell function. What controls the dynamics of peroxisomal membranes, and how this influences the dynamics of the peroxisomes themselves, is just beginning to be understood. In this review, we consider how the composition, biophysical properties, and protein-lipid interactions of peroxisomal membranes impacts on their dynamics, and in turn on the biogenesis and function of peroxisomes. In particular, we focus on the effect of the peroxin PEX11 on the peroxisome membrane, and its function as a major regulator of growth and division. Understanding the roles and regulation of peroxisomal membrane dynamics necessitates a multidisciplinary approach, encompassing knowledge across a range of model species and a number of fields including lipid biochemistry, biophysics and computational biology. Here, we present an integrated overview of our current understanding of the determinants of peroxisome membrane dynamics, and reflect on the outstanding questions still remaining to be solved.
PubMed: 35185625
DOI: 10.3389/fphys.2022.834411 -
Frontiers in Cell and Developmental... 2021Peroxisomes are ubiquitous, single membrane-bound organelles that play a crucial role in lipid metabolism and human health. While peroxisome number is maintained by the... (Review)
Review
Peroxisomes are ubiquitous, single membrane-bound organelles that play a crucial role in lipid metabolism and human health. While peroxisome number is maintained by the division of existing peroxisomes, nascent peroxisomes can be generated from the endoplasmic reticulum (ER) membrane in yeasts. During formation and proliferation, peroxisomes maintain membrane contacts with the ER. In addition to the ER, contacts between peroxisomes and other organelles such as lipid droplets, mitochondria, vacuole, and plasma membrane have been reported. These membrane contact sites (MCS) are dynamic and important for cellular function. This review focuses on the recent developments in peroxisome biogenesis and the functional importance of peroxisomal MCS in yeasts.
PubMed: 34869317
DOI: 10.3389/fcell.2021.735031 -
Biochimica Et Biophysica Acta Sep 2012Peroxisomes are remarkably dynamic, multifunctional organelles, which react to physiological changes in their cellular environment and adopt their morphology, number,... (Review)
Review
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.
Topics: Animals; Dynamins; GTP Phosphohydrolases; Humans; Intracellular Membranes; Membrane Proteins; Microtubule-Associated Proteins; Mitochondrial Dynamics; Mitochondrial Proteins; PPAR alpha; Peroxisomal Disorders; Peroxisomes; Protein Isoforms; Signal Transduction
PubMed: 22240198
DOI: 10.1016/j.bbadis.2011.12.014 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are highly dynamic organelles that can rapidly change in size, abundance, and protein content in response to alterations in nutritional and other... (Review)
Review
Peroxisomes are highly dynamic organelles that can rapidly change in size, abundance, and protein content in response to alterations in nutritional and other environmental conditions. These dynamic changes in peroxisome features, referred to as peroxisome dynamics, rely on the coordinated action of several processes of peroxisome biogenesis. Revealing the regulatory mechanisms of peroxisome dynamics is an emerging theme in cell biology. These mechanisms are inevitably linked to and synchronized with the biogenesis and degradation of peroxisomes. To date, the key players and basic principles of virtually all steps in the peroxisomal life cycle are known, but regulatory mechanisms remained largely elusive. A number of recent studies put the spotlight on reversible protein phosphorylation for the control of peroxisome dynamics and highlighted peroxisomes as hubs for cellular signal integration and regulation. Here, we will present and discuss the results of several studies performed using yeast and mammalian cells that convey a sense of the impact protein phosphorylation may have on the modulation of peroxisome dynamics by regulating peroxisomal matrix and membrane protein import, proliferation, inheritance, and degradation. We further put forward the idea to make use of current data on phosphorylation sites of peroxisomal and peroxisome-associated proteins reported in advanced large-scale phosphoproteomic studies.
Topics: Animals; Autophagy; Gene Expression Regulation; Glycerol-3-Phosphate Dehydrogenase (NAD+); Humans; Membrane Proteins; Membrane Transport Proteins; Mice; Organelle Biogenesis; Peroxisomal Targeting Signal 2 Receptor; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Phosphorylation; Protein Isoforms; Protein Transport; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 26775584
DOI: 10.1016/j.bbamcr.2015.12.022 -
Biochimica Et Biophysica Acta May 2016In mammals, peroxisomes perform crucial functions in cellular metabolism, signalling and viral defense which are essential to the health and viability of the organism.... (Review)
Review
In mammals, peroxisomes perform crucial functions in cellular metabolism, signalling and viral defense which are essential to the health and viability of the organism. In order to achieve this functional versatility peroxisomes dynamically respond to molecular cues triggered by changes in the cellular environment. Such changes elicit a corresponding response in peroxisomes, which manifests itself as a change in peroxisome number, altered enzyme levels and adaptations to the peroxisomal structure. In mammals the generation of new peroxisomes is a complex process which has clear analogies to mitochondria, with both sharing the same division machinery and undergoing a similar division process. How the regulation of this division process is integrated into the cell's response to different stimuli, the signalling pathways and factors involved, remains somewhat unclear. Here, we discuss the mechanism of peroxisomal fission, the contributions of the various division factors and examine the potential impact of post-translational modifications, such as phosphorylation, on the proliferation process. We also summarize the signalling process and highlight the most recent data linking signalling pathways with peroxisome proliferation.
Topics: Animals; Biological Transport; Dynamins; Endoplasmic Reticulum; Eukaryotic Cells; GTP Phosphohydrolases; Gene Expression Regulation; Humans; Membrane Proteins; Microtubule-Associated Proteins; Mitochondrial Proteins; Mutation; Organelle Biogenesis; Peroxins; Peroxisomes; Plants; Protein Isoforms; Protein Structure, Tertiary; Saccharomyces cerevisiae Proteins; Signal Transduction; Yeasts
PubMed: 26409486
DOI: 10.1016/j.bbamcr.2015.09.024 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are ubiquitous organelles of eukaryotic cells, and it is becoming increasingly clear that the biogenesis of these multi-purpose organelles is more complex... (Review)
Review
Peroxisomes are ubiquitous organelles of eukaryotic cells, and it is becoming increasingly clear that the biogenesis of these multi-purpose organelles is more complex than initially anticipated. Along this line, peroxisomes exhibit features, which clearly distinguish them from other cellular organelles, like their ability to import folded proteins or their capability to form de novo. However, further insight into the cellular life of peroxisomes also revealed features that they share with other organelles, such as organelle fission or regulated degradation by autophagy, that are similar for peroxisomes, mitochondria and chloroplasts. This special issue highlights recent progress in the understanding of the biogenesis of peroxisomes with emphasis on the assembly, maintenance and dynamics of the organelles. In particular, it focuses on the following areas: (i) topogenesis of peroxisomal matrix proteins as well as the structure and function of peroxisomal protein import machineries. (ii) Peroxisomal targeting of membrane proteins and de novo formation of peroxisomes. (iii) Maintenance of peroxisomes in health and disease. (iv) Proliferation and regulated degradation of peroxisomes. (v) Motility and inheritance of peroxisomes. (vi) Role of peroxisomes in the cellular context.
Topics: Animals; Autophagy; Eukaryotic Cells; Humans; Intracellular Membranes; Membrane Fusion; Membrane Proteins; Organelle Biogenesis; Peroxisomes; Protein Transport
PubMed: 26851075
DOI: 10.1016/j.bbamcr.2016.01.020 -
Nature Communications Aug 2022Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles,...
Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles, MCSs remain largely unexplored during infections. Here, we design a targeted proteomics platform for measuring MCS proteins at all organelles simultaneously and define functional virus-driven MCS alterations by the ancient beta-herpesvirus human cytomegalovirus (HCMV). Integration with super-resolution microscopy and comparisons to herpes simplex virus (HSV-1), Influenza A, and beta-coronavirus HCoV-OC43 infections reveals time-sensitive contact regulation that allows switching anti- to pro-viral organelle functions. We uncover a stabilized mitochondria-ER encapsulation structure (MENC). As HCMV infection progresses, MENCs become the predominant mitochondria-ER contact phenotype and sequentially recruit the tethering partners VAP-B and PTPIP51, supporting virus production. However, premature ER-mitochondria tethering activates STING and interferon response, priming cells against infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested.
Topics: Cytomegalovirus; Cytomegalovirus Infections; Herpes Simplex; Herpesviridae Infections; Humans; Organelles; Peroxisomes; Viruses
PubMed: 35953480
DOI: 10.1038/s41467-022-32488-6 -
Frontiers in Cell and Developmental... 2020Research using the fruit fly has traditionally focused on understanding how mutations affecting gene regulation or function affect processes linked to animal... (Review)
Review
Research using the fruit fly has traditionally focused on understanding how mutations affecting gene regulation or function affect processes linked to animal development. Accordingly, flies have become an essential foundation of modern medical research through repeated contributions to our fundamental understanding of how their homologs of human genes function. Peroxisomes are organelles that metabolize lipids and reactive oxygen species like peroxides. However, despite clear linkage of mutations in human genes affecting peroxisomes to developmental defects, for many years fly models were conspicuously absent from the study of peroxisomes. Now, the few early studies linking the Rosy eye color phenotype to peroxisomes in flies have been joined by a growing body of research establishing novel roles for peroxisomes during the development or function of specific tissues or cell types. Similarly, unique properties of cultured fly Schneider 2 cells have advanced our understanding of how peroxisomes move on the cytoskeleton. Here, we profile how those past and more recent studies started to link specific effects of peroxisome dysfunction to organ development and highlight the utility of flies as a model for human peroxisomal diseases. We also identify key differences in the function and proliferation of fly peroxisomes compared to yeast or mammals. Finally, we discuss the future of the fly model system for peroxisome research including new techniques that should support identification of additional tissue specific regulation of and roles for peroxisomes.
PubMed: 32984330
DOI: 10.3389/fcell.2020.00835 -
Biochimica Et Biophysica Acta Jun 2010Peroxisomes perform a wide variety of metabolic processes in eukaryotic organisms. Mutations that affect peroxisome function or formation have profound phenotypic... (Review)
Review
Peroxisomes perform a wide variety of metabolic processes in eukaryotic organisms. Mutations that affect peroxisome function or formation have profound phenotypic consequences, the latter demonstrated by peroxisome biogenesis disorders which are often fatal. The biogenesis of peroxisomes conceptually consists of: (1) the formation of the peroxisomal membrane, (2) the import of peroxisomal matrix enzymes and (3) the proliferation of the organelles. Proteins involved in these processes are collectively called peroxins, encoded by PEX-genes. To date 32 peroxins are known, which perform functions in peroxisome biogenesis that are conserved from yeast to man. In this article, we focus on the current status of knowledge about the topogenesis of the peroxisomal membrane proteins, and the import of proteins into the peroxisomal matrix.
Topics: Animals; Cell Membrane; Cytoplasm; Cytosol; Endoplasmic Reticulum; Humans; Models, Biological; Peroxisomes; Protein Structure, Tertiary; Protein Transport; Saccharomyces cerevisiae; Signal Transduction; Ubiquitin
PubMed: 20079383
DOI: 10.1016/j.bbamcr.2010.01.002