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EMBO Reports Oct 2021Zellweger spectrum disorder (ZSD) is the most severe peroxisomal biogenesis disorder (PBD). Why ZSD patients not only loose functional peroxisomes but also present with...
Zellweger spectrum disorder (ZSD) is the most severe peroxisomal biogenesis disorder (PBD). Why ZSD patients not only loose functional peroxisomes but also present with severe mitochondrial dysfunction was a long-standing mystery. In this issue, Nuebel et al (2021) identified that loss of peroxisomes leads to re-routing of peroxisomal proteins to mitochondria, thereby impairing mitochondrial structure and function. The findings provide the first molecular understanding of the mitochondrial-peroxisomal link in ZSD.
Topics: Humans; Mitochondria; Peroxins; Peroxisomal Disorders; Peroxisomes; Zellweger Syndrome
PubMed: 34414648
DOI: 10.15252/embr.202153790 -
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 -
Oxidative Medicine and Cellular... 2022The absence of peroxisomes can cause disease in the human reproductive system, including the ovaries. The available peroxisomal gene-knockout female mouse models, which... (Review)
Review
The absence of peroxisomes can cause disease in the human reproductive system, including the ovaries. The available peroxisomal gene-knockout female mouse models, which exhibit pathological changes in the ovary and reduced fertility, are listed in this review. Our review article provides the first systematic presentation of peroxisomal regulation and its possible functions in the ovary. Our immunofluorescence results reveal that peroxisomes are present in all cell types in the ovary; however, peroxisomes exhibit different numerical abundances and strong heterogeneity in their protein composition among distinct ovarian cell types. The peroxisomal compartment is strongly altered during follicular development and during oocyte maturation, which suggests that peroxisomes play protective roles in oocytes against oxidative stress and lipotoxicity during ovulation and in the survival of oocytes before conception. In addition, the peroxisomal compartment is involved in steroid synthesis, and peroxisomal dysfunction leads to disorder in the sexual hormone production process. However, an understanding of the cellular and molecular mechanisms underlying these physiological and pathological processes is lacking. To date, no effective treatment for peroxisome-related disease has been developed, and only supportive methods are available. Thus, further investigation is needed to resolve peroxisome deficiency in the ovary and eventually promote female fertility.
Topics: Animals; Cell Differentiation; Cell Proliferation; Female; Fertility; Gene Knockout Techniques; Humans; Mice; Oocytes; Ovarian Follicle; Ovulation; Oxidative Stress; Peroxisomes; Signal Transduction; Steroids
PubMed: 35154572
DOI: 10.1155/2022/7982344 -
Biology Direct Sep 2023Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell-type-specific manner. However, the mechanisms by which the status of...
Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell-type-specific manner. However, the mechanisms by which the status of peroxisomes is communicated and integrated into cellular signaling pathways are not yet understood. Herein, we report the cellular responses to peroxisomal proteotoxic stress upon silencing the peroxisomal protease/chaperone LONP2. Depletion of LONP2 triggered the accumulation of its substrate TYSND1 protease, while the overall expression of peroxisomal proteins, as well as TYSND1-dependent ACOX1 processing appeared normal, reflecting early stages of peroxisomal proteotoxic stress. Consequently, the alteration of peroxisome size and numbers, and luminal protein import failure was coupled with induction of cell-specific cellular stress responses. Specific to COS-7 cells was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These unexpected consequences of peroxisomal stress provide an important insight into our understanding of the tissue-specific responses seen in peroxisomal disorders.
Topics: Signal Transduction; Endosomes; Ribosomes; Peptide Hydrolases; Up-Regulation
PubMed: 37736739
DOI: 10.1186/s13062-023-00416-3 -
Indian Pediatrics Jul 2022
Topics: Chondrodysplasia Punctata, Rhizomelic; Humans; Rare Diseases
PubMed: 35869882
DOI: No ID Found -
Autophagy Dec 2021Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their...
Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their transcriptional co-activators are involved in autophagy. We thus examined MED1 (mediator complex subunit 1), a key component of the Mediator Complex that directly interacts with NRs, on these processes. We found that knockdown (KD) in cultured hepatic cells decreased autophagy and mitochondrial activity that was accompanied by decreased transcription of genes involved in these processes. Lipophagy and fatty acid β-oxidation also were impaired. These effects also occurred after thyroid hormone stimulation, nutrient-replete or -deplete conditions, and in liver-specific KD ( LKD) mice under fed and fasting conditions. Together, these findings showed that played a key role in hepatic autophagy, mitochondria function, and lipid metabolism under these conditions. Additionally, we identified downregulated hepatic genes in LKD mice, and subjected them to ChIP Enrichment Analysis. Our findings showed that the transcriptional activity of several NRs and transcription factors (TFs), including PPARA and FOXO1, likely were affected by LKD. Finally, expression and autophagy also were decreased in two mouse models of nonalcoholic fatty liver disease (NAFLD) suggesting that decreased may contribute to hepatosteatosis. In summary, plays an essential role in regulating hepatic autophagy and lipid oxidation during different hormonal and nutrient conditions. Thus, may serve as an integrator of multiple transcriptional pathways involved in these metabolic processes. BAF: bafilomycin A; db/db mice; mice; ECAR: extracellular acidification rate; KD: knockdown; MED1: mediator complex subunit 1; NAFLD: nonalcoholic fatty liver disease; OCR: oxygen consumption rate; PPARA/PPARα: peroxisomal proliferator activated receptor alpha; TF: transcription factor; TFEB: transcription factor EB; tf-LC3: tandem fluorescence RFP-GFP-LC3; TG: triglyceride; TH: Thyroid hormone; TR: thyroid hormone receptors; V-ATPase: vacuolar-type H-ATPase; WDF: Western diet with 15% fructose in drinking water.
Topics: Animals; Autophagy; Lipid Metabolism; Liver; Mediator Complex Subunit 1; Mice; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 33734012
DOI: 10.1080/15548627.2021.1899691 -
Ophthalmology Science Jun 2021Peroxisomal biogenesis disorders (PBDs) represent a spectrum of conditions that result in vision loss, sensorineural hearing loss, neurologic dysfunction, and other...
PURPOSE
Peroxisomal biogenesis disorders (PBDs) represent a spectrum of conditions that result in vision loss, sensorineural hearing loss, neurologic dysfunction, and other abnormalities resulting from aberrant peroxisomal function caused by mutations in genes. With no treatments currently available, we sought to investigate the disease mechanism in a patient with a PBD caused by defects in and to probe whether overexpression of could restore peroxisome function and potentially offer therapeutic benefit.
DESIGN
Laboratory-based study.
PARTICIPANTS
A 12-year-old boy sought treatment with hearing loss and retinopathy. After negative results in an Usher syndrome panel, targeted genetic testing revealed compound heterozygous mutations in . These included a 14-nucleotide deletion (c.802_815del: p.(Asp268Cysfs∗8)) and a milder missense variant (c.35T→C:(p.Phe12Ser)).
METHODS
Patient-derived skin fibroblasts were cultured, and a knockout cell line was developed using clustered regularly interspaced short palindromic repeats and Cas9 technology in HEK293T cells to emulate a more severe disease phenotype. Immunoblot analysis of whole cell lysates was performed to assess peroxisome number. Immunofluorescence studies used antibodies against components of the peroxisomal protein import pathway to interrogate the effects of mutations in on protein trafficking.
MAIN OUTCOME MEASURES
Primary outcome measures were peroxisome abundance and matrix protein import.
RESULTS
Peroxisome number was not significantly different between control fibroblasts and patient fibroblasts; however, fewer peroxisomes were observed in knockout cells compared with wild-type cells ( = 0.04). Analysis by immunofluorescent microscopy showed significantly impaired peroxisomal targeting signal 1- and peroxisomal targeting signal 2-mediated matrix protein import in both patient fibroblasts and knockout cells. Overexpressing resulted in improved matrix protein import in knockout cells.
CONCLUSIONS
Mutations in were responsible for combined hearing loss and retinopathy in our patient. The primary peroxisomal defect in our patient's skin fibroblasts was impaired peroxisomal protein import as opposed to reduction in the number of peroxisomes. Genetic strategies that introduce wild-type into cells deficient in PEX6 protein show promise in restoring peroxisome function. Future studies of patient-specific induced pluripotent stem cell-derived retinal pigment epithelium cells may clarify the role of in the retina and the potential for gene therapy in these patients.
PubMed: 36249295
DOI: 10.1016/j.xops.2021.100028 -
Frontiers in Immunology 2020Mevalonate kinase deficiency (MKD) is an inborn error of metabolism leading to a syndrome characterized by recurrent inflammation. This clinically manifests itself as... (Review)
Review
Mevalonate kinase deficiency (MKD) is an inborn error of metabolism leading to a syndrome characterized by recurrent inflammation. This clinically manifests itself as fever and can be accompanied by gastrointestinal symptoms, oral ulcers, cervical lymphadenopathy, and skin rash. We searched Pubmed, Embase, Cochrane, and CINAHL for relevant articles. All articles were screened by both authors. Relevant articles were included in this review. The interleukin-1 antagonist canakinumab is the only well-studied and effective treatment for MKD patients with 35% of patients reaching complete remission in a large randomized controlled trial. Other therapeutic options include glucocorticoids and the IL-1 antagonist anakinra, although the level of evidence for these treatments is weaker. If patients fail to these treatments, the biologicals etanercept or tocilizumab can be used. Mildly affected patients might benefit from cheaper, less invasive treatments such as paracetamol and NSAIDs. Canakinumab is the only evidence-based treatment for mevalonate kinase deficiency. However, the costs limit availability for many patients. Cheaper and more readily available options include glucocorticoids, anakinra, etanercept, and tocilizumab, although there is limited evidence supporting these treatments.
Topics: Child; Child, Preschool; Female; Humans; Immunologic Factors; Male; Mevalonate Kinase Deficiency
PubMed: 32582214
DOI: 10.3389/fimmu.2020.01150 -
International Journal of Molecular... Apr 2021Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases... (Review)
Review
Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or β-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors.
Topics: Animals; Disease Models, Animal; Metabolome; Peroxisomes; Phospholipids; Retina; Retinal Diseases
PubMed: 33921065
DOI: 10.3390/ijms22084101 -
Frontiers in Molecular Neuroscience 2023Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM)...
Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders.
PubMed: 37138705
DOI: 10.3389/fnmol.2023.1170313