Peroxisomes are dispensable for normal renal function.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE179202 | GEO | 2022/03/02
REPOSITORIES: GEO
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Project description:Peroxisomal Biogenesis Disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger Spectrum Disorder (ZSD)—is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
2021-06-13 | GSE159869 | GEO
Project description:Peroxisomal Biogenesis Disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger Spectrum Disorder(ZSD)—is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
2021-05-10 | PXD025595 | Pride
Project description:Peroxisomes are organelles that are crucial for cellular metabolism. However, these organelles play also important roles in non-metabolic processes, such as signalling. To uncover the consequences of peroxisome deficiency, we compared two extremes, namely Saccharomyces cerevisiae wild-type and pex3 cells, which lack functional peroxisomes, employing transcriptomics and quantitative proteomics technology. Cells were grown on acetate, a carbon source that involves peroxisomal enzymes of the glyoxylate cycle and does not repress peroxisomal proteins. Transcripts of peroxisomal β-oxidation genes and the corresponding proteins were enhanced in pex3 cells. Peroxisome-deficiency also caused reduced levels of membrane bound peroxins, while the soluble receptors Pex5 and Pex7 were enhanced at the protein level. In addition, we observed alterations in non-peroxisomal transcripts and proteins, especially mitochondrial proteins involved in respiration or import processes. Our results not only reveal the impact of the absence of peroxisomes in yeast, but also represent a rich resource of candidate genes/proteins that are relevant in peroxisome biology.
2024-05-01 | GSE261289 | GEO
Project description:Peroxisomes are membrane-bound organelles that help cells specialize their metabolism. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. Thus, we performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that transcriptional inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), dramatically reduced the import of proteins into peroxisomes. The observed RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerase tankyrase, which binds the peroxisomal membrane protein PEX14. We propose a model in which RNF146 and tankyrase regulate peroxisome import efficiency by tuning PARsylation of proteins at the peroxisome membrane. Interestingly, we found that perturbations to peroxisomes altered tankyrase’s selection of substrates, including the beta-catenin destruction complex component AXIN1. The loss of peroxisomes caused tankyrase and RNF146-dependent degradation of AXIN1 and a concomitant increase of beta-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation, but also a novel role in bridging peroxisome function with Wnt/beta-catenin signaling during development.
2024-06-01 | GSE266892 | GEO
Project description:Peroxisomes are membrane-bound organelles that help cells specialize their metabolism. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. Thus, we performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that transcriptional inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), dramatically reduced the import of proteins into peroxisomes. The observed RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerase tankyrase, which binds the peroxisomal membrane protein PEX14. We propose a model in which RNF146 and tankyrase regulate peroxisome import efficiency by tuning PARsylation of proteins at the peroxisome membrane. Interestingly, we found that perturbations to peroxisomes altered tankyrase’s selection of substrates, including the beta-catenin destruction complex component AXIN1. The loss of peroxisomes caused tankyrase and RNF146-dependent degradation of AXIN1 and a concomitant increase of beta-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation, but also a novel role in bridging peroxisome function with Wnt/beta-catenin signaling during development.
2024-06-01 | GSE266855 | GEO
Project description:E. histolytica is believed to be devoid of peroxisomes, like most anaerobic protists. In this work, we provided the first evidence that peroxisomes are present in E. histolytica, although the set of proteins (peroxins) responsible for peroxisome biogenesis was reduced to only seven members (Pex1, Pex6, Pex5, Pex11, Pex14, Pex16, and Pex19). Targeting matrix proteins to peroxisomes is reduced to the PTS1-dependent pathway mediated via the soluble Pex5 receptor, while the PTS2 receptor Pex7 is absent. Immunofluorescence microscopy showed that peroxisomal markers (Pex5, Pex14, Pex16, Pex19) are present in vesicles distinct from mitosomes, the endoplasmic reticulum and the endosome/phagosome system, except Pex11, which has dual localization in peroxisomes and mitosomes. Immunoelectron microscopy revealed that Pex14 localized to vesicles of approximately 90-100 nm in diameter. Proteomic analyses of affinity-purified peroxisomes and in silico PTS1 predictions provided datasets of 655 and 56 peroxisomal candidates, respectively; however, only six proteins were shared by both datasets, including myo-inositol dehydrogenase (myo-IDH). Peroxisomal NAD-dependent myo-IDH appeared to be a dimeric enzyme with high affinity to myo-inositol (Km 0,044 mM) and can utilize also scyllo-inositol, D-glucose and D-xylose as substrates. Phylogenetic analyses revealed that orthologs of myo-IDH with PTS1 are present in E. dispar, E. nutalli and E. moshkovskii but not in E. invadens, and form a monophyletic clade of mostly peroxisomal orthologs with free-living M. balamuthi and P. schiedti. The presence of peroxisomes in E. histolytica and other archamoebae breaks the paradigm of peroxisome absence in anaerobes and provides a new potential target for the development of antiparasitic drugs.
2021-10-29 | PXD026653 | Pride
Project description:Detection of viral RNA in the cytosol of infected cells depends on RIG-I-lilke recptors that use MAVS as an adapter protein to activate antiviral gene expression. MAVS is tail-anchored on mitochondria, mitochondria-associated membranes and peroxisomes. As peroxisomal membrane proteins can be mistargeted to mitochondria in the absence of peroxisomes, we hypothesized that MAVS-dependent antiviral gene expression is activated more efficiently in this instance. Pex19 deficient skin firoblasts derived from a Zellweger syndrome patient lack peroxisomes. We introduced wild type Pex19 into these cells to restore peroxisome formation and assessed alterations in the gene expression profile of these cells after reovirus infection.
2014-04-15 | GSE56783 | GEO
Project description:Detection of viral RNA in the cytosol of infected cells depends on RIG-I-lilke recptors that use MAVS as an adapter protein to activate antiviral gene expression. MAVS is tail-anchored on mitochondria, mitochondria-associated membranes and peroxisomes. As peroxisomal membrane proteins can be mistargeted to mitochondria in the absence of peroxisomes, we hypothesized that MAVS-dependent antiviral gene expression is activated more efficiently in this instance. Pex19 deficient skin firoblasts derived from a Zellweger syndrome patient lack peroxisomes. We introduced wild type Pex19 into these cells to restore peroxisome formation and assessed alterations in the gene expression profile of these cells after reovirus infection. 6 samples: 9 and 16 hrs after reovirus infection at an MOI of 100 total RNA was extracted from Pex19 reconstituted and deficient cell lines. Gene expression data was compared to uninfected cells.
2014-04-15 | E-GEOD-56783 | biostudies-arrayexpress
Project description:FOXO transcription factors control cellular formation of reactive oxygen species (ROS), which critically contribute to cell survival and cell death in neuroblastoma. Here, we report that C10orf10, also named M-bM-^@M-^\Decidual Protein induced by Progesterone (DEPP)M-bM-^@M-^], is a direct transcriptional target of FOXO3 in human neuroblastoma. As FOXO3-mediated apoptosis involves a biphasic ROS accumulation, we analyzed cellular ROS levels in DEPP-knockdown cells by live-cell imaging. Knockdown of DEPP prevented the primary and secondary ROS accumulation during FOXO3 activation and attenuates FOXO3-induced apoptosis, whereas its overexpression raises cellular ROS levels and sensitizes to cell death. In neuronal cells, cellular steady state ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that enables protein import into peroxisomes, we analyzed the effect of DEPP on peroxisomal function by measuring the catalase enzyme activity. Catalase activity was reduced by conditional DEPP overexpression and significantly increased in DEPP-knockdown cells. Using live cell imaging and fluorescent peroxisomal and mitochondrial probes we demonstrate that DEPP localizes to peroxisomes and mitochondria in neuroblastoma cells. The combined data indicate that DEPP reduces peroxisomal activity and thereby impairs the cellular ROS detoxification capacity and contributes to death sensitization. SH-EP, NB15 neuroblastoma cells and CCRF-CEM-C7H2 acute lymphoblastic leukemia cells were infected with the retrovirus plasmid pLIB-FOXO3(A3)-Ertm-iresNeo. Gene expression measures of samples with activated FOXO3 transcription factor (3h OHT treated) have been compared to untreated samples (0h time point). To rule out gene regulations by estrogen samples treated for 3 hours with tamoxifen have been compared to the untreated samples. Only genes that were more than two-fold regulated in the first, but not in the second comparison were defined to be FOXO3 regulated.
2014-10-06 | E-GEOD-53046 | biostudies-arrayexpress
Project description:FOXO transcription factors control cellular formation of reactive oxygen species (ROS), which critically contribute to cell survival and cell death in neuroblastoma. Here, we report that C10orf10, also named “Decidual Protein induced by Progesterone (DEPP)”, is a direct transcriptional target of FOXO3 in human neuroblastoma. As FOXO3-mediated apoptosis involves a biphasic ROS accumulation, we analyzed cellular ROS levels in DEPP-knockdown cells by live-cell imaging. Knockdown of DEPP prevented the primary and secondary ROS accumulation during FOXO3 activation and attenuates FOXO3-induced apoptosis, whereas its overexpression raises cellular ROS levels and sensitizes to cell death. In neuronal cells, cellular steady state ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that enables protein import into peroxisomes, we analyzed the effect of DEPP on peroxisomal function by measuring the catalase enzyme activity. Catalase activity was reduced by conditional DEPP overexpression and significantly increased in DEPP-knockdown cells. Using live cell imaging and fluorescent peroxisomal and mitochondrial probes we demonstrate that DEPP localizes to peroxisomes and mitochondria in neuroblastoma cells. The combined data indicate that DEPP reduces peroxisomal activity and thereby impairs the cellular ROS detoxification capacity and contributes to death sensitization. SH-EP, NB15 neuroblastoma cells and CCRF-CEM-C7H2 acute lymphoblastic leukemia cells were infected with the retrovirus plasmid pLIB-FOXO3(A3)-Ertm-iresNeo.
2014-10-06 | GSE53046 | GEO