-
The Journal of Biological Chemistry Aug 2023Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles, physically connected at membrane contact sites. While collaborating in lipid...
Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles, physically connected at membrane contact sites. While collaborating in lipid metabolism, for example, of very long-chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in peroxisome biogenesis. Recent work identified tethering complexes on the ER and peroxisome membranes that connect the organelles. These include membrane contacts formed via interactions between the ER protein VAPB (vesicle-associated membrane protein-associated protein B) and the peroxisomal proteins ACBD4 and ACBD5 (acyl-coenzyme A-binding domain protein). Loss of ACBD5 has been shown to cause a significant reduction in peroxisome-ER contacts and accumulation of VLCFAs. However, the role of ACBD4 and the relative contribution these two proteins make to contact site formation and recruitment of VLCFAs to peroxisomes remain unclear. Here, we address these questions using a combination of molecular cell biology, biochemical, and lipidomics analyses following loss of ACBD4 or ACBD5 in HEK293 cells. We show that the tethering function of ACBD5 is not absolutely required for efficient peroxisomal β-oxidation of VLCFAs. We demonstrate that loss of ACBD4 does not reduce peroxisome-ER connections or result in the accumulation of VLCFAs. Instead, the loss of ACBD4 resulted in an increase in the rate of β-oxidation of VLCFAs. Finally, we observe an interaction between ACBD5 and ACBD4, independent of VAPB binding. Overall, our findings suggest that ACBD5 may act as a primary tether and VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in peroxisomal lipid metabolism at the peroxisome-ER interface.
Topics: Humans; Adaptor Proteins, Signal Transducing; Endoplasmic Reticulum; HEK293 Cells; Lipid Metabolism; Membrane Proteins; Mitochondrial Membranes; Peroxisomes
PubMed: 37414147
DOI: 10.1016/j.jbc.2023.105013 -
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 -
Postepy Biochemii Dec 2018Peroxisomes are multifunctional microorganelles that play a key role in numerous biochemical processes adapting dynamically to the current physiological requirements of... (Review)
Review
Peroxisomes are multifunctional microorganelles that play a key role in numerous biochemical processes adapting dynamically to the current physiological requirements of the cell. The disturbance of the peroxisome structure due to mutations in different PEX and non-PEX genes coding functional peroxisomal proteins is the pathogenic basis of the peroxisomal disorders. The β-oxidation process of very long-chain fatty acids (VLCFA) is a unique metabolic pathway located exclusively in the peroxisome. This determines that VLCFA is the main biomarker for the diagnosis of peroxisomal diseases. Peroxisomal disorders present a broad spectrum of clinical symptoms from the neonatal, severe Zellweger syndrome with dysmorphia, multi-organ dysfunction to the late symptomatic adult form of X-linked adrenoleukodystrophy. Relatively common the use of highly specialized analytical techniques causes it is a still growing group of rare metabolic diseases.
Topics: Adrenoleukodystrophy; Fatty Acids; Humans; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Zellweger Syndrome
PubMed: 30656921
DOI: 10.18388/pb.2018_150 -
International Journal of Molecular... May 2017Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have... (Review)
Review
Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles. This review provides a comprehensive look of what is currently known about the interconnectivity between peroxisomes and mitochondria within mammalian cells. We first outline how peroxisomal and mitochondrial abundance are controlled by common sets of - and -acting factors. Next, we discuss how peroxisomes and mitochondria may communicate with each other at the molecular level. In addition, we reflect on how these organelles cooperate in various metabolic and signaling pathways. Finally, we address why peroxisomes and mitochondria have to maintain a healthy relationship and why defects in one organelle may cause dysfunction in the other. Gaining a better insight into these issues is pivotal to understanding how these organelles function in their environment, both in health and disease.
Topics: Animals; Cellular Senescence; Fatty Acids; Humans; Metabolic Networks and Pathways; Mitochondria; Oxidation-Reduction; Peroxisomes; Reactive Oxygen Species; Signal Transduction
PubMed: 28538669
DOI: 10.3390/ijms18061126 -
Antioxidants & Redox Signaling Aug 2016Peroxisomes are organelles present in most eukaryotic cells. The organs with the highest density of peroxisomes are the liver and kidneys. Peroxisomes possess more than... (Review)
Review
SIGNIFICANCE
Peroxisomes are organelles present in most eukaryotic cells. The organs with the highest density of peroxisomes are the liver and kidneys. Peroxisomes possess more than fifty enzymes and fulfill a multitude of biological tasks. They actively participate in apoptosis, innate immunity, and inflammation. In recent years, a considerable amount of evidence has been collected to support the involvement of peroxisomes in the pathogenesis of kidney injury.
RECENT ADVANCES
The nature of the two most important peroxisomal tasks, beta-oxidation of fatty acids and hydrogen peroxide turnover, functionally relates peroxisomes to mitochondria. Further support for their communication and cooperation is furnished by the evidence that both organelles share the components of their division machinery. Until recently, the majority of studies on the molecular mechanisms of kidney injury focused primarily on mitochondria and neglected peroxisomes.
CRITICAL ISSUES
The aim of this concise review is to introduce the reader to the field of peroxisome biology and to provide an overview of the evidence about the contribution of peroxisomes to the development and progression of kidney injury. The topics of renal ischemia-reperfusion injury, endotoxin-induced kidney injury, diabetic nephropathy, and tubulointerstitial fibrosis, as well as the potential therapeutic implications of peroxisome activation, are addressed in this review.
FUTURE DIRECTIONS
Despite recent progress, further studies are needed to elucidate the molecular mechanisms induced by dysfunctional peroxisomes and the role of the dysregulated mitochondria-peroxisome axis in the pathogenesis of renal injury. Antioxid. Redox Signal. 25, 217-231.
Topics: Animals; Autophagy; Disease Models, Animal; Fatty Acids; Homeostasis; Humans; Kidney; Kidney Diseases; Oxidation-Reduction; Oxidative Stress; Peroxisomes; Reactive Oxygen Species
PubMed: 26972522
DOI: 10.1089/ars.2016.6666 -
Biochimica Et Biophysica Acta May 2016The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure... (Review)
Review
The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure to import the enzymes in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation although it only rarely determines the clinical fate. In mouse models of these diseases liver pathologies also occur, although these are not always concordant with the human phenotype which might be due to differences in diet, expression of enzymes and backup mechanisms. Besides the morphological changes, we overview the impact of peroxisome malfunction on other cellular compartments including mitochondria and the ER. We further focus on the metabolic pathways that are affected such as bile acid formation, and dicarboxylic acid and branched chain fatty acid degradation. It appears that the association between deregulated metabolites and pathological events remains unclear.
Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum; Gene Expression Regulation; Humans; Liver; Membrane Proteins; Metabolic Networks and Pathways; Mice; Mitochondria, Liver; Mutation; Peroxisomal Disorders; Peroxisomes; Protein Isoforms; Protein Transport; Signal Transduction
PubMed: 26453805
DOI: 10.1016/j.bbamcr.2015.09.035 -
Biochimica Et Biophysica Acta May 2016Attachment of peroxisomes to cytoskeleton and movement along microtubular filaments and actin cables are essential and highly regulated processes enabling metabolic... (Review)
Review
Attachment of peroxisomes to cytoskeleton and movement along microtubular filaments and actin cables are essential and highly regulated processes enabling metabolic efficiency, biogenesis, maintenance and inheritance of this dynamic cellular compartment. Several peroxisome-associated proteins have been identified, which mediate interaction with motor proteins, adaptor proteins or other constituents of the cytoskeleton. It appears that there is a species-specific complexity of protein-protein interactions required to control directional movement and arresting. An open question is why some proteins with a specific role in peroxisomal protein import have an additional function in the regulation of cytoskeleton binding and motility of peroxisomes.
Topics: Actin Cytoskeleton; Biological Transport; Gene Expression Regulation; Humans; Membrane Proteins; Microtubules; Myosin Heavy Chains; Myosin Type V; Organelle Biogenesis; Peroxins; Peroxisomes; Protein Isoforms; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 26616035
DOI: 10.1016/j.bbamcr.2015.11.022 -
The Journal of Clinical Investigation Oct 2023Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a...
Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.
Topics: Humans; Peroxisomes; Lipid Metabolism; Melanoma; Ceramides
PubMed: 37616051
DOI: 10.1172/JCI166644 -
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 -
Cell Reports Oct 2023The enhanced response of glucagon and its Drosophila homolog, adipokinetic hormone (Akh), leads to high-caloric-diet-induced hyperglycemia across species. While previous...
The enhanced response of glucagon and its Drosophila homolog, adipokinetic hormone (Akh), leads to high-caloric-diet-induced hyperglycemia across species. While previous studies have characterized regulatory components transducing linear Akh signaling promoting carbohydrate production, the spatial elucidation of Akh action at the organelle level still remains largely unclear. In this study, we find that Akh phosphorylates extracellular signal-regulated kinase (ERK) and translocates it to peroxisome via calcium/calmodulin-dependent protein kinase II (CaMKII) cascade to increase carbohydrate production in the fat body, leading to hyperglycemia. The mechanisms include that ERK mediates fat body peroxisomal conversion of amino acids into carbohydrates for gluconeogenesis in response to Akh. Importantly, Akh receptor (AkhR) or ERK deficiency, importin-associated ERK retention from peroxisome, or peroxisome inactivation in the fat body sufficiently alleviates high-sugar-diet-induced hyperglycemia. We also observe mammalian glucagon-induced hepatic ERK peroxisomal translocation in diabetic subjects. Therefore, our results conclude that the Akh/glucagon-peroxisomal-ERK axis is a key spatial regulator of glycemic control.
Topics: Animals; Carbohydrates; Drosophila; Extracellular Signal-Regulated MAP Kinases; Glucagon; Glycemic Control; Hyperglycemia; Peroxisomes; Drosophila Proteins
PubMed: 37796662
DOI: 10.1016/j.celrep.2023.113200