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Frontiers in Physiology Nov 2013Although peroxisomes are ubiquitous organelles in all animal species, their importance for the functioning of tissues and organs remains largely unresolved. Because... (Review)
Review
Although peroxisomes are ubiquitous organelles in all animal species, their importance for the functioning of tissues and organs remains largely unresolved. Because peroxins are essential for the biogenesis of peroxisomes, an obvious approach to investigate their physiological role is to inactivate a Pex gene or to suppress its translation. This has been performed in mice but also in more primitive organisms including D. melanogaster, C. elegans, and D. rerio, and the major findings and abnormalities in these models will be highlighted. Although peroxisomes are generally not essential for embryonic development and organogenesis, a generalized inactivity of peroxisomes affects lifespan and posthatching/postnatal growth, proving that peroxisomal metabolism is necessary for the normal maturation of these organisms. Strikingly, despite the wide variety of model organisms, corresponding tissues are affected including the central nervous system and the testis. By inactivating peroxisomes in a cell type selective way in the brain of mice, it was also demonstrated that peroxisomes are necessary to prevent neurodegeneration. As these peroxisome deficient model organisms recapitulate pathologies of patients affected with peroxisomal diseases, their further analysis will contribute to the elucidation of still elusive pathogenic mechanisms.
PubMed: 24319432
DOI: 10.3389/fphys.2013.00335 -
Orphanet Journal of Rare Diseases May 2023The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused...
Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
BACKGROUND
The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused by deficiencies in peroxisome function and are segmented into enzyme-and-transporter defects (defects in single peroxisomal proteins) and peroxisome biogenesis disorders (defects in the peroxin proteins, critical for normal peroxisome assembly and biogenesis). In this study, we employed multivariate supervised and non-supervised statistical methods and utilized mass spectrometry data of neurological patients, peroxisomal disorder patients (X-linked adrenoleukodystrophy and Zellweger syndrome), and healthy controls to analyze the role of common metabolites in peroxisomal disorders, to develop and refine a classification models of X-linked adrenoleukodystrophy and Zellweger syndrome, and to explore analytes with utility in rapid screening and diagnostics.
RESULTS
T-SNE, PCA, and (sparse) PLS-DA, operated on mass spectrometry data of patients and healthy controls were utilized in this study. The performance of exploratory PLS-DA models was assessed to determine a suitable number of latent components and variables to retain for sparse PLS-DA models. Reduced-features (sparse) PLS-DA models achieved excellent classification performance of X-linked adrenoleukodystrophy and Zellweger syndrome patients.
CONCLUSIONS
Our study demonstrated metabolic differences between healthy controls, neurological patients, and peroxisomal disorder (X-linked adrenoleukodystrophy and Zellweger syndrome) patients, refined classification models and showed the potential utility of hexacosanoylcarnitine (C26:0-carnitine) as a screening analyte for Chinese patients in the context of a multivariate discriminant model predictive of peroxisomal disorders.
Topics: Child; Humans; Adrenoleukodystrophy; East Asian People; Multivariate Analysis; Peroxisomal Disorders; Zellweger Syndrome; China
PubMed: 37189159
DOI: 10.1186/s13023-023-02673-x -
FEBS Letters Jun 2000Peroxisome assembly in mammals requires more than 15 genes. Two isoforms of the peroxisome targeting signal type 1 (PTS1) receptor, Pex5pS and Pex5pL, are identified in... (Review)
Review
Peroxisome assembly in mammals requires more than 15 genes. Two isoforms of the peroxisome targeting signal type 1 (PTS1) receptor, Pex5pS and Pex5pL, are identified in mammals. Pex5pS and Pex5pL bind PTS1 proteins. Pex5pL, but not Pex5pS, directly interacts with the PTS2 receptor, Pex7p, carrying its cargo PTS2 protein in the cytosol. Pex5p carrying the cargos, PTS1 and PTS2, docks with the initial site Pex14p in a putative import machinery, subsequently translocating to other components such as Pex13p, Pex2p, Pex10p and Pex12p, whereby the matrix proteins are imported. The peroxins, Pex3p, Pex16p and Pex19p, function in the assembly of peroxisomal membrane vesicles that precedes the import of matrix proteins. Hence, peroxisomes may form de novo and do not have to arise from pre-existing, morphologically recognizable peroxisomes. Impaired peroxisome assembly causes peroxisome biogenesis disorders such as Zellweger syndrome.
Topics: Animals; Humans; Intracellular Membranes; Mammals; Models, Biological; Peroxisomal Disorders; Peroxisomal Targeting Signal 2 Receptor; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Receptors, Cytoplasmic and Nuclear
PubMed: 10878247
DOI: 10.1016/s0014-5793(00)01667-7 -
Molecules and Cells Jan 2018Autophagy is an intracellular degradation pathway for large protein aggregates and damaged organelles. Recent studies have indicated that autophagy targets cargoes... (Review)
Review
Autophagy is an intracellular degradation pathway for large protein aggregates and damaged organelles. Recent studies have indicated that autophagy targets cargoes through a selective degradation pathway called selective autophagy. Peroxisomes are dynamic organelles that are crucial for health and development. Pexophagy is selective autophagy that targets peroxisomes and is essential for the maintenance of homeostasis of peroxisomes, which is necessary in the prevention of various peroxisome-related disorders. However, the mechanisms by which pexophagy is regulated and the key players that induce and modulate pexophagy are largely unknown. In this review, we focus on our current understanding of how pexophagy is induced and regulated, and the selective adaptors involved in mediating pexophagy. Furthermore, we discuss current findings on the roles of pexophagy in physiological and pathological responses, which provide insight into the clinical relevance of pexophagy regulation. Understanding how pexophagy interacts with various biological functions will provide fundamental insights into the function of pexophagy and facilitate the development of novel therapeutics against peroxisomal dysfunction-related diseases.
Topics: Animals; Autophagy; Endoplasmic Reticulum; Humans; Membrane Proteins; Mitochondria; Models, Biological; Peroxisomes; Zellweger Syndrome
PubMed: 29370694
DOI: 10.14348/molcells.2018.2245 -
Orphanet Journal of Rare Diseases Jul 2022Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms...
BACKGROUND
Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive.
METHODS
We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations.
RESULTS
Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration.
CONCLUSIONS
This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.
Topics: Genetic Association Studies; Humans; Membrane Proteins; Mutation; Peroxisomes; Zellweger Syndrome
PubMed: 35854306
DOI: 10.1186/s13023-022-02415-5 -
The EMBO Journal Jun 2020Primary cilia are antenna-like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis....
Primary cilia are antenna-like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis. Cellular cholesterol functions as a direct activator of a seven-transmembrane oncoprotein called Smoothened (Smo) and thereby induces Smo accumulation on the ciliary membrane where it transduces the Shh signal. However, how cholesterol is supplied to the ciliary membrane remains unclear. Here, we report that peroxisomes are essential for the transport of cholesterol into the ciliary membrane. Zellweger syndrome (ZS) is a peroxisome-deficient hereditary disorder with several ciliopathy-related features and cells from these patients showed a reduced cholesterol level in the ciliary membrane. Reverse genetics approaches revealed that the GTP exchange factor Rabin8, the Rab GTPase Rab10, and the microtubule minus-end-directed kinesin KIFC3 form a peroxisome-associated complex to control the movement of peroxisomes along microtubules, enabling communication between peroxisomes and ciliary pocket membranes. Our findings suggest that insufficient ciliary cholesterol levels may underlie ciliopathies.
Topics: Cells, Cultured; Cholesterol; Cilia; Germinal Center Kinases; Humans; Kinesins; Microtubules; Smoothened Receptor; Zellweger Syndrome; rab GTP-Binding Proteins
PubMed: 32368833
DOI: 10.15252/embj.2019103499 -
Molecular Genetics and Metabolism Nov 2021Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms.... (Review)
Review
Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.
Topics: Adult; Clinical Trials as Topic; Disease Management; Humans; Longitudinal Studies; Phenotype; Zellweger Syndrome
PubMed: 34625341
DOI: 10.1016/j.ymgme.2021.09.007 -
Biochimica Et Biophysica Acta Dec 2006Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their... (Review)
Review
Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their chemical structures were described and their effect on membrane fluidity and membrane fusion discussed. The recent generation of mouse models with ether lipid deficiency offered the possibility to study ether lipid and particularly plasmalogen functions in vivo. Ether lipid-deficient mice revealed severe phenotypic alterations, including arrest of spermatogenesis, development of cataract and defects in central nervous system myelination. In several cell culture systems lack of plasmalogens impaired intracellular cholesterol distribution affecting plasma membrane functions and structural changes of ER and Golgi cisternae. Based on these phenotypic anomalies that were accurately described conclusions were drawn on putative functions of plasmalogens. These functions were related to cell-cell or cell-extracellular matrix interactions, formation of lipid raft microdomains and intracellular cholesterol homeostasis. There are several human disorders, such as Zellweger syndrome, rhizomelic chondrodysplasia punctata, Alzheimer's disease, Down syndrome, and Niemann-Pick type C disease that are distinguished by altered tissue plasmalogen concentrations. The role plasmalogens might play in the pathology of these disorders is discussed.
Topics: Acyltransferases; Animals; Cataract; Cell Membrane; Cholesterol; Endoplasmic Reticulum; Golgi Apparatus; Hereditary Central Nervous System Demyelinating Diseases; Lens, Crystalline; Male; Membrane Fluidity; Membrane Fusion; Mice; Mice, Knockout; Peroxisomal Targeting Signal 2 Receptor; Plasmalogens; Receptors, Cytoplasmic and Nuclear; Spermatogenesis
PubMed: 17027098
DOI: 10.1016/j.bbamcr.2006.08.038 -
Frontiers in Cell and Developmental... 2023
PubMed: 36711036
DOI: 10.3389/fcell.2023.1136992 -
European Heart Journal. Cardiovascular... May 2023
Topics: Humans; Pheochromocytoma; Takotsubo Cardiomyopathy; Syndrome; Adrenal Gland Neoplasms
PubMed: 37014047
DOI: 10.1093/ehjci/jead053