-
International Journal of Molecular... Jan 2022Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is...
Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of mice in better understanding disease mechanism in fatty acid α-oxidation disorders.
Topics: Animals; Brain; Carbon-Carbon Lyases; Cytochrome P450 Family 2; Cytochrome P450 Family 4; Fatty Acids; Female; Gene Knockout Techniques; Kidney; Lipidomics; Liver; Male; Mice; Oxidation-Reduction; Peroxisomes; Phytanic Acid; Phytol; Proteomics
PubMed: 35055171
DOI: 10.3390/ijms23020987 -
Biochimie Mar 2014Peroxisome proliferator-activated receptor-α (PPARα) modulates the activities of all three interlinked hepatic fatty acid oxidation systems, namely mitochondrial and... (Review)
Review
Peroxisome proliferator-activated receptor-α (PPARα) modulates the activities of all three interlinked hepatic fatty acid oxidation systems, namely mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation pathways. Hyperactivation of PPARα, by both exogenous and endogenous activators up-regulates hepatic fatty acid oxidation resulting in excess energy burning in liver contributing to the development of liver cancer in rodents. Sustained PPARα signaling disproportionately increases H2O2-generating fatty acid metabolizing enzymes as compared to H2O2-degrading enzymes in liver leading to enhanced generation of DNA damaging reactive oxygen species, progressive endoplasmic reticulum stress and inflammation. These alterations also contribute to increased liver cell proliferation with changes in apoptosis. Thus, reactive oxygen species, oxidative stress and hepatocellular proliferation are likely the main contributing factors in the pathogenesis of hepatocarcinogenesis, mediated by sustained PPARα activation-related energy burning in liver. Furthermore, the transcriptional co-activator Med1, a key subunit of the Mediator complex, is essential for PPARα signaling in that both PPARα-null and Med1-null hepatocytes are unresponsive to PPARα activators and fail to give rise to liver tumors when chronically exposed to PPARα activators.
Topics: Animals; Cell Proliferation; Energy Metabolism; Fatty Acids; Liver; Liver Neoplasms; Mediator Complex Subunit 1; Mice; Mice, Knockout; MicroRNAs; Oxidation-Reduction; Oxidative Stress; PPAR alpha; Peroxisome Proliferators; Peroxisomes
PubMed: 24291192
DOI: 10.1016/j.biochi.2013.11.011 -
Frontiers in Cell and Developmental... 2022Peroxisomes are present in eukaryotic cells and have essential roles in various biological processes. Plant peroxisomes proliferate by biosynthesis or division of... (Review)
Review
Peroxisomes are present in eukaryotic cells and have essential roles in various biological processes. Plant peroxisomes proliferate by biosynthesis or division of pre-existing peroxisomes, degrade, or replace metabolic enzymes, in response to developmental stages, environmental changes, or external stimuli. Defects of peroxisome functions and biogenesis alter a variety of biological processes and cause aberrant plant growth. Traditionally, peroxisomal function-based screening has been employed to isolate mutants that are defective in peroxisomal metabolism, such as lipid degradation and photorespiration. These analyses have revealed that the number, subcellular localization, and activity of peroxisomes are closely related to their efficient function, and the molecular mechanisms underlying peroxisome dynamics including organelle biogenesis, protein transport, and organelle interactions must be understood. Various approaches have been adopted to identify factors involved in peroxisome dynamics. With the development of imaging techniques and fluorescent proteins, peroxisome research has been accelerated. Image-based analyses provide intriguing results concerning the movement, morphology, and number of peroxisomes that were hard to obtain by other approaches. This review addresses image-based analysis of peroxisome dynamics in plants, especially and .
PubMed: 35592252
DOI: 10.3389/fcell.2022.883491 -
Plant Signaling & Behavior Jul 2007Plant peroxisomes are highly dynamic organelles that adapt to environmental variation by altering their number, but the molecular basis for plant peroxisome...
Plant peroxisomes are highly dynamic organelles that adapt to environmental variation by altering their number, but the molecular basis for plant peroxisome proliferation is largely unknown. To begin understanding how this fundamental cell biological process is controlled in plants, we recently characterized the Arabidopsis homologues of the yeast Pex11p protein, which is involved in peroxisome proliferation via an unknown mechanism. Using a combination of fluorescence microscopy, immunobiochemistry, overexpression and loss-of-function studies, and heterologous gene expression in yeast cells, we showed that all five Arabidopsis PEX11 proteins target to peroxisomal membranes and promote peroxisome proliferation with partial redundancy and specificity. A subset of the dynamin-related proteins (DRPs) is also involved with peroxisome division in plants, yeast, and mammals. Future experiments should focus on addressing the biochemical function of PEX11 and using new tools to uncover additional components of the peroxisome proliferation pathways, especially those that are unique to plants.
PubMed: 19704631
DOI: 10.4161/psb.2.4.4070 -
The Plant Cell Jan 2007PEROXIN11 (PEX11) is a peroxisomal membrane protein in fungi and mammals and was proposed to play a major role in peroxisome proliferation. To begin understanding how...
PEROXIN11 (PEX11) is a peroxisomal membrane protein in fungi and mammals and was proposed to play a major role in peroxisome proliferation. To begin understanding how peroxisomes proliferate in plants and how changes in peroxisome abundance affect plant development, we characterized the extended Arabidopsis thaliana PEX11 protein family, consisting of the three phylogenetically distinct subfamilies PEX11a, PEX11b, and PEX11c to PEX11e. All five Arabidopsis PEX11 proteins target to peroxisomes, as demonstrated for endogenous and cyan fluorescent protein fusion proteins by fluorescence microscopy and immunobiochemical analysis using highly purified leaf peroxisomes. PEX11a and PEX11c to PEX11e behave as integral proteins of the peroxisome membrane. Overexpression of At PEX11 genes in Arabidopsis induced peroxisome proliferation, whereas reduction in gene expression decreased peroxisome abundance. PEX11c and PEX11e, but not PEX11a, PEX11b, and PEX11d, complemented to significant degrees the growth phenotype of the Saccharomyces cerevisiae pex11 null mutant on oleic acid. Heterologous expression of PEX11e in the yeast mutant increased the number and reduced the size of the peroxisomes. We conclude that all five Arabidopsis PEX11 proteins promote peroxisome proliferation and that individual family members play specific roles in distinct peroxisomal subtypes and environmental conditions and possibly in different steps of peroxisome proliferation.
Topics: Arabidopsis; Arabidopsis Proteins; Genetic Complementation Test; Intracellular Membranes; Luminescent Proteins; Membrane Proteins; Molecular Sequence Data; Multigene Family; Peroxins; Peroxisomes; Phenotype; Phylogeny; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 17220199
DOI: 10.1105/tpc.106.045831 -
Archives of Biochemistry and Biophysics May 1991The existence of a relationship between clofibrate-induced peroxisome proliferation and oxidative stress mediated by activated oxygen species was studied in intact...
The existence of a relationship between clofibrate-induced peroxisome proliferation and oxidative stress mediated by activated oxygen species was studied in intact peroxisomes purified from Pisum sativum L. plants. Incubation of leaves with 1 mM clofibrate produced a remarkable increase in the peroxisomal activity of acyl-CoA oxidase and, to a lesser extent, of xanthine oxidase, whereas there was a nearly complete loss of catalase activity and a decrease in Mn-superoxide dismutase. Ultrastructural studies of intact leaves showed that clofibrate induced a five- and twofold proliferation of the peroxisomal and mitochondrial populations, respectively, in comparison with those in control leaves. Prolonged incubation with clofibrate produced considerable alterations in the ultrastructure of cells. In peroxisomal membranes, the NADH-induced generation of O2- radicals, as well as the lipid peroxidation of membranes, increased as a result of treatment of plants with clofibrate. In intact peroxisomes treated with this hypolipidemic drug, the H2O2 concentration was higher than in peroxisomes from control plants. These results demonstrate that clofibrate stimulates the production of activated oxygen species (O2- and H2O2) inside peroxisomes, as well as the lipid peroxidation of peroxisomal membranes. This effect is concomitant with a decrease of catalase and Mn-SOD activities, the main peroxisomal enzymatic defenses against H2O2 and O2-, and indicates that in the toxicity of clofibrate, at the level of peroxisomes, an oxidative stress mechanism mediated by activated oxygen species is involved.
Topics: Clofibrate; Fabaceae; Microbodies; Microscopy, Electron; Oxidation-Reduction; Oxygen; Plants, Medicinal
PubMed: 1897996
DOI: 10.1016/0003-9861(91)90389-z -
Journal of Biochemistry Mar 2017Pex19p harbouring a prenylation CAAX box functions as a chaperone and transporter for peroxisomal membrane proteins in membrane assembly. By functional...
Pex19p harbouring a prenylation CAAX box functions as a chaperone and transporter for peroxisomal membrane proteins in membrane assembly. By functional phenotype-complementation assay using a pex19 Chinese hamster ovary cell mutant ZP119, we herein cloned a rat cDNA encoding a protein similar to Pex19p, but with a C-terminal hydrophobic segment in place of the CAAX box region. The transcript of this gene was highly induced by treatment of rats with a peroxisome proliferator, clofibrate, hence termed PEX19i, while the other three less prominently inducible PEX19 variants encoded authentic Pex19p but differed in the length of 3' non-coding region. Pex19pi restored peroxisomes in ZP119 with slightly lower efficiency than Pex19p, showing apparently weaker interaction with Pex11pβ essential for peroxisome proliferation. However, the C-terminal region of Pex19p was not essential for the association of Pex19p with peroxisomal membrane and interaction with membrane assembly factors, Pex3p and Pex16p. Non-prenylated Pex19p interacted with a membrane protein cargo, Pex14p, but more weakly than Pex19pi and the farnesylated Pex19p. Thus, PEX19i most likely plays important roles involving the membrane formation at early stages, in prompt response to peroxisome proliferation. Similar types of PEX19 mRNA variants were also elevated in mouse regenerating liver.
Topics: Alternative Splicing; Animals; CHO Cells; Cricetulus; Genetic Variation; Male; Molecular Chaperones; Peroxisomes; Rats; Rats, Wistar
PubMed: 28391327
DOI: 10.1093/jb/mvw075 -
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 2012Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger... (Review)
Review
Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. Thirteen of these genes are associated with ZSS disorders. The genetic heterogeneity among PBDs and the inability to predict from the biochemical and clinical phenotype of a patient with ZSS which of the currently known 13 PEX genes is defective, has fostered the development of different strategies to identify the causative gene defects. These include PEX cDNA transfection complementation assays followed by sequencing of the thus identified PEX genes, and a PEX gene screen in which the most frequently mutated exons of the different PEX genes are analyzed. The benefits of DNA testing for PBDs include carrier testing of relatives, early prenatal testing or preimplantation genetic diagnosis in families with a recurrence risk for ZSS disorders, and insight in genotype-phenotype correlations, which may eventually assist to improve patient management. In this review we describe the current status of genetic analysis and the molecular basis of PBDs.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Female; Genetic Association Studies; Humans; Membrane Proteins; Molecular Diagnostic Techniques; Mutation; Peroxisomal Disorders; Peroxisomes; Pregnancy; Prenatal Diagnosis; Protein Transport
PubMed: 22871920
DOI: 10.1016/j.bbadis.2012.04.006 -
Environmental Pollution (Barking, Essex... Jan 2023Perfluorooctanoic acid (PFOA) is a widespread persistent organic pollutant. Fertile chicken eggs were exposed to PFOA and incubated to hatch. At three time points post...
Perfluorooctanoic acid (PFOA) is a widespread persistent organic pollutant. Fertile chicken eggs were exposed to PFOA and incubated to hatch. At three time points post hatch (0-, 1- and 3-months old), chickens were subjected to electrocardiography and sacrificed. Serum was subjected to LC-MS/MS for PFOA concentration, and organs were subjected to histopathological assessments. Additionally, PPARα-silencing lentivirus was co-applied with PFOA exposure, and the corresponding phenotypes were evaluated. Western blotting was performed to assess expressions of FABPs and pSMAD2 in heart and liver samples. Considerable amount of PFOA were detected in hatchling chicken serum, but not in one-month-old or three-month-old chicken serum. PFOA exposure resulted in developmental cardiotoxicity and hepatotoxicity in hatchling chickens. Meanwhile, one-month-old chickens still exhibited elevated heart rate, but classical cardiac remodeling (thicker right ventricular wall) were observed in exposed animals. Three-month-old chickens exhibited similar results as one-month-old ones. PPARα silencing only had partial protective effects in hatchling chickens, but the protective effects seemed to increase as chickens aged. Western blotting results indicated that L-FABP was involved in PFOA-induced hepatotoxicity, while pSMAD2 was involved in PFOA-induced cardiotoxicity. In summary, developmental exposure to PFOA resulted in persistent cardiotoxicity, but not hepatotoxicity. PPARα participates in both cardiotoxicity and hepatotoxicity.
Topics: Animals; Chickens; Cardiotoxicity; PPAR alpha; Chromatography, Liquid; Peroxisomes; Tandem Mass Spectrometry; Caprylates; Fluorocarbons; Cell Proliferation; Liver
PubMed: 36436667
DOI: 10.1016/j.envpol.2022.120722