Peroxisomal Metabolism Research Articles

Peroxisome Metabolism in Cancer.

Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redox balance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid synthesis, bile acid synthesis, and reactive oxygen species homeostasis. Human disorders caused by genetic mutations in peroxisome genes have led to extensive studies on peroxisome biology. Peroxisomal defects are linked to metabolic dysregulation in diverse human diseases, such as neurodegeneration and age-related disorders, revealing the significance of peroxisome metabolism in human health. Cancer is a disease with metabolic aberrations. Despite the critical role of peroxisomes in cell metabolism, the functional effects of peroxisomes in cancer are not as well recognized as those of other metabolic organelles, such as mitochondria. In addition, the significance of peroxisomes in cancer is less appreciated than it is in degenerative diseases. In this review, I summarize the metabolic pathways in peroxisomes and the dysregulation of peroxisome metabolism in cancer. In addition, I discuss the potential of inactivating peroxisomes to target cancer metabolism, which may pave the way for more effective cancer treatment.

Phytanic acid-derived peroxisomal lipid metabolism in porcine oocytes

Lipid metabolism plays an important role in oocyte maturation. The peroxisome is the fundamental mediator for this mechanism. In this study, we investigated the peroxisomal lipid metabolism in porcine oocytes. Phytanic acid (PA) was chosen as an activator of alpha-oxidation in peroxisomes. Oocyte maturation, embryo development, immunocytochemistry of peroxisomal lipid activities, and staining of mitochondrial potentials were assessed. We found that 40 μM PA not only increased porcine oocyte maturation and embryonic development, but also upregulated the expression of genes and proteins related to activities of the peroxisomal lipid metabolism (PHYH, PEX19, and PEX subfamilies) and mitochondrial potentials (NRF1 and PGC1α). Moreover, PA upregulated the lipid droplet and fatty acid content in the oocytes. Moreover, mitochondria were activated and the mitochondrial membrane potential was increased after PA treatment, resulting in the production of more ATPs in the oocytes. Our findings suggest that the degradation of PA via alpha-oxidation in the peroxisome may potentiate oocyte maturation processes, peroxisomal lipid oxidation, and mitochondria activities.

Plant Peroxisomes: A Factory of Reactive Species.

Plant peroxisomes are organelles enclosed by a single membrane whose biochemical composition has the capacity to adapt depending on the plant tissue, developmental stage, as well as internal and external cellular stimuli. Apart from the peroxisomal metabolism of reactive oxygen species (ROS), discovered several decades ago, new molecules with signaling potential, including nitric oxide (NO) and hydrogen sulfide (H2S), have been detected in these organelles in recent years. These molecules generate a family of derived molecules, called reactive nitrogen species (RNS) and reactive sulfur species (RSS), whose peroxisomal metabolism is autoregulated through posttranslational modifications (PTMs) such as S-nitrosation, nitration and persulfidation. The peroxisomal metabolism of these reactive species, which can be weaponized against pathogens, is susceptible to modification in response to external stimuli. This review aims to provide up-to-date information on crosstalk between these reactive species families and peroxisomes, as well as on their cellular environment in light of the well-recognized signaling properties of H2O2, NO and H2S.

Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver

Feeding of rapeseed (canola) oil with a high erucic acid concentration is known to cause hepatic steatosis in animals. Mitochondrial fatty acid oxidation plays a central role in liver lipid homeostasis, so it is possible that hepatic metabolism of erucic acid might decrease mitochondrial fatty acid oxidation. However, the precise mechanistic relationship between erucic acid levels and mitochondrial fatty acid oxidation is unclear. Using male Sprague-Dawley rats, along with biochemical and molecular biology approaches, we report here that peroxisomal β-oxidation of erucic acid stimulates malonyl-CoA formation in the liver and thereby suppresses mitochondrial fatty acid oxidation. Excessive hepatic uptake and peroxisomal β-oxidation of erucic acid resulted in appreciable peroxisomal release of free acetate, which was then used in the synthesis of cytosolic acetyl-CoA. Peroxisomal metabolism of erucic acid also remarkably increased the cytosolic NADH/NAD+ ratio, suppressed sirtuin 1 (SIRT1) activity, and thereby activated acetyl-CoA carboxylase, which stimulated malonyl-CoA biosynthesis from acetyl-CoA. Chronic feeding of a diet including high-erucic-acid rapeseed oil diminished mitochondrial fatty acid oxidation and caused hepatic steatosis and insulin resistance in the rats. Of note, administration of a specific peroxisomal β-oxidation inhibitor attenuated these effects. Our findings establish a cross-talk between peroxisomal and mitochondrial fatty acid oxidation. They suggest that peroxisomal oxidation of long-chain fatty acids suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation, which might play a role in fatty acid-induced hepatic steatosis and related metabolic disorders.

Peroxisomal Metabolism and Dynamics at the Crossroads Between Stimulus Perception and Fast Cell Responses to the Environment.

This study was co-funded by MCIU, AEI, FEDER grant PGC2018-098372-B-I00. The authors acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through URICI. MP-V was supported by Research Personnel Training (FPI) fellowship from the Spanish MCIU (BEJ-2016-076518).

Short-term inhibition of autophagy benefits pancreatic β-cells by augmenting ether lipids and peroxisomal function, and by countering depletion of n-3 polyunsaturated fatty acids after fat-feeding

ObjectiveInvestigations of autophagy in β-cells have usually focused on its homeostatic function. More dynamic roles in inhibiting glucose-stimulated insulin secretion (GSIS), potentially involving remodelling of cellular lipids, have been suggested from in vitro studies but not evaluated in vivo. MethodsWe employed temporally-regulated deletion of the essential autophagy gene, Atg7, in β-cells. Mice were fed chow or high-fat diets (HFD), in conjunction with deletion of Atg7 for the last 3 weeks (short-term model) or 9 weeks (long-term model). Standard in vivo metabolic phenotyping was undertaken, and 450 lipid species in islets quantified ex vivo using mass spectroscopy (MS). MIN6 cells were also employed for lipidomics and secretory interventions. Resultsβ-cell function was impaired by inhibiting autophagy in the longer-term, but conversely improved by 3-week deletion of Atg7, specifically under HFD conditions. This was accompanied by augmented GSIS ex vivo. Surprisingly, the HFD had minimal effect on sphingolipid and neutral lipid species, but modulated >100 phospholipids and ether lipids, and markedly shifted the profile of polyunsaturated fatty acid (PUFA) sidechains from n3 to n6 forms. These changes were partially countered by Atg7 deletion, consistent with an accompanying upregulation of the PUFA elongase enzyme, Elovl5. Loss of Atg7 separately augmented plasmalogens and alkyl lipids, in association with increased expression of Lonp2, a peroxisomal chaperone/protease that facilitates maturation of ether lipid synthetic enzymes. Depletion of PUFAs and ether lipids was also observed in MIN6 cells chronically exposed to oleate (more so than palmitate). GSIS was inhibited by knocking down Dhrs7b, which encodes an enzyme of peroxisomal ether lipid synthesis. Conversely, impaired GSIS due to oleate pre-treatment was selectively reverted by Dhrs7b overexpression. ConclusionsA detrimental increase in n6:n3 PUFA ratios in ether lipids and phospholipids is revealed as a major response of β-cells to high-fat feeding. This is partially reversed by short-term inhibition of autophagy, which results in compensatory changes in peroxisomal lipid metabolism. The short-term phenotype is linked to improved GSIS, in contrast to the impairment seen with the longer-term inhibition of autophagy. The balance between these positive and negative inputs could help determine whether β-cells adapt or fail in response to obesity.

SUN-LB40 Chronic Cortisol Works Through the Transcription Factor KLF9 to Deregulate Immune Response and Metabolism

Chronically elevated levels of glucocorticoids (GC) are associated with a number of disease states and negative side effects, including metabolic syndrome. Epidemiological studies show that elevated GC during a brief but vulnerable developmental window can have life-long and potentially multi-generational impacts on health. To elucidate underlying pathogenic mechanisms, our lab has used chronic treatment with a physiological dosage of cortisol (CORT) in developing zebrafish, Danio rerio, a model organism that has emerged as a useful tool for investigating GC signaling. In this paradigm, we have found evidence that high CORT during development alters a set point for the HPA axis and leads to continuous induction of aberrant GC production and transport, accompanied by altered immune gene regulation and decreased ability to maintain blood glucose homeostasis. To identify molecular and genetic pathways perturbed by chronic CORT treatment, we used CRISPR to generate mutant lines lacking the glucocorticoid receptor (GR) or the transcription factor Klf9, which we have found to be an important target/regulator of GC signaling. We performed RNA sequencing in these mutant lines and compared the transcriptomes of wild type (WT) and mutant animals treated with either chronic CORT or vehicle control (VEH). A broad overview of the data shows similarities between CORT treated wild-type fish and VEH treated GR mutants suggestive of GC resistance in the CORT treated WT animals. In Klf9 mutants, a number of genes involved in immune processes that were upregulated by chronic CORT in WT animals were not similarly upregulated, suggesting that Klf9 is an important feed-forward mediator of immune gene regulation by GC. Additionally, CORT increased expression of a number of metabolic genes in Klf9 mutants that were not similarly upregulated in WT, suggesting that Klf9 plays a regulatory role in the response of cellular metabolism to GC. To further investigate Klf9’s role in governing cellular metabolism, metabolic rate assays were performed on live animals. The results show that Klf9 mutants have lower total respiration, and that chronic CORT increases non-mitochondrial respiration in both WT and Klf9 mutants. Mitochondrial respiratory capacity was unaffected across conditions. This, coupled with gene expression data, suggests that measured metabolic differences are due to shifts in substrate usage and differential reliance on non-mitochondrial metabolic pathways such as glycolsis and peroxisomal beta-oxidation. Additional studies are required, but the regulation of glycolysis by Klf9 could contribute to this gene’s known tumor-suppresive role, and regulation of peroxisomal metabolism—key in immune cells—could partially explain the role of Klf9 in mediating these cells’ responsiveness to CORT.

Dried Blood Spot-Based Metabolomic Profiling in Adults with Cystic Fibrosis

Mucoviscidosis of the respiratory, gastrointestinal, and genitourinary tracts is the major pathology in patients with cystic fibrosis (CF), a lethal monogenic panethnic and multisystemic disease most commonly identified in Caucasians. Currently, the measurement of immuno reactive trypsinogen in dry blood spots (DBSs) is the gold-standard method for initial newborn screening for CF, followed by targeted CF transmembrane regulator (CFTR) mutation analysis, and ultimate confirmation with abnormally elevated sweat chloride. Previous metabolomics studies in patients with CF reported on different biomarkers such as breath 2-aminoacetophenone produced during acute and chronic infection in human tissues, including the lungs of CF patients. Herein, we used liquid and gas chromatography-mass spectrometry-based targeted metabolomics profiling to identify potentially reliable, sensitive, and specific biomarkers in DBSs collected from 69 young and adult people including CF patients (n = 39) and healthy control (n = 30). A distinctive metabolic profile including 26 significantly differentially expressed metabolites involving amino acids, glycolysis, mitochondrial and peroxisomal metabolism, and sorbitol pathways was identified. Specifically, the osmolyte (sorbitol) was remarkably downregulated in CF patients compared to healthy controls indicating perturbation in the sorbitol pathway, which may be responsible for the mucoviscidosis seen in patients with CF. The significance of our findings is supported by the clinical utility of inhaled mannitol and hypertonic saline in patients with CF. The systemic administration of sorbitol in such patients may confer additional benefits beyond the respiratory system, especially in those with misfolded CFTR proteins.

The Role of Coenzyme A Degradation in the Regulation of Peroxisomal Metabolism

Coenzyme A (CoA) is an essential metabolic cofactor that activates fatty acids and other organic acids as CoA thioesters for a multitude of metabolic pathways in different subcellular compartments. For example, CoA is utilized in the bile acid synthesis pathway and for shortening of very long chain fatty acids in the peroxisomes. The regulation of CoA levels is essential to maintain metabolic flexibility in response to changes in nutritional status and energy demands. Balance between CoA synthesis and degradation is responsible for the regulation of CoA. While CoA synthesis is controlled at the pantothenate kinase step, the intracellular degradation of CoA is controlled by Nudix hydrolases. Nudt7 is a hepatic, peroxisomal Nudix hydrolase that specifically hydrolyzes CoA species into 3’,5’‐ADP and (acyl)phosphopantetheine. Nudt7 displays a broad substrate specificity; it is active against free CoA, short‐ and medium‐chain acyl‐CoAs, including acetyl‐CoA, and the acyl‐CoA derivatives of bile acids. Nudt7 expression and activity are regulated by nutritional state, as they both decrease upon fasting. Overexpression of Nudt7 in the liver was recently found to decrease the levels of a variety of short‐chain acyl‐CoAs and choloyl‐CoA in the liver, and to decrease the rate of peroxisomal β‐oxidation. To gain further insight into the role of Nudt7 in vivo, Nudt7−/− mice were generated and their lipid metabolism assessed. Deletion of Nudt7 caused a small but significant increase in total hepatic CoA levels in the fasted state. In particular, higher concentrations of malonyl‐and acetyl‐CoA were observed. Furthermore, livers from Nudt7−/− males contained higher levels of short‐chain fatty acids and short‐chain acylcarnitines, which, combined, suggest an increase in fatty acid oxidation. In the fed state, female Nudt7−/− mice exhibited a higher concentration of selected bile acids in the intestine, while feeding of a high fat high/cholesterol diet resulted in higher bile acid levels in the liver. This increase in bile acids occurred without changes in the expression of genes involved in bile acid synthesis or transport and without a correspondent increase in the concentration of bile acid precursors 7α‐hydroxycholesterol and 7α‐hydroxycholestenone. These results suggest that higher CoA levels in the peroxisomes may mediate an increase in flux through the bile acid biosynthetic pathway by activating of the last, peroxisomal steps in the pathway.Overall, analysis of lipid metabolism following manipulation of Nudt7 expression in mouse liver indicates that this enzyme contributes to the regulation of peroxisomal fatty acids and bile acid metabolism.Support or Funding InformationThis work was supported by West Virginia University’s School of Medicine startup foundation funding and NIH grant GM119528.

Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Peroxisomal disorders are a clinically and genetically heterogeneous group of diseases caused by defects in peroxisomal biogenesis or function, usually impairing several metabolic pathways. Peroxisomal disorders are rare; however, the incidence may be underestimated due to the broad spectrum of clinical presentations. The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform Screening Panel for newborn screening programs in the United States may increase detection of this and other peroxisomal disorders. The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long–chain and branched-chain fatty acids in plasma and plasmalogens in red bloodcells. Molecular testing can confirm biochemical findings and identify the specific genetic defect, usually utilizing a multiple-gene panel or exome/genome approach. When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction. This document provides a resource for laboratories developing and implementing clinical biochemical genetic testing for peroxisomal disorders, emphasizing technical considerations for sample collection, test performance, and result interpretation. Additionally, considerations on confirmatory molecular testing are discussed.

NUDT7 Loss Promotes KrasG12D CRC Development

Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7−/−) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7−/− and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7−/− colons. Upregulated levels of β-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7−/− mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7−/− mice. We observed an increased level of palmitic acid in the colon of Nudt7−/− mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.

Proteomics Analysis of Colostrum Samples from Sows Housed under Different Conditions

Simple SummaryMilk quality in sows is affected by various factors, including the living environment. However, changes in protein-expression profiles in the milk of sows housed under different conditions are still unclear. Accordingly, in this study, we performed proteomics analysis of colostrum from sows housed under different conditions. Our results showed that housing conditions affected protein expression, and the effects of housing conditions were observed in both pregnancy and lactation. In comparison, the differentially expressed proteins were related to the immune system and metabolic processes, particularly fat metabolism. These results revealed the physiological changes in sows under different housing conditions. Overall, these findings provided important insights into the care and management of sows to enhance milk quality.This study investigated the proteomic characteristics of colostrum for sows housed under different conditions. Among 12 gilts, four were housed in a gestation-crate and farrowing-crate combined housing system (CC) as controls, four were housed in a gestation-pen and farrowing-pen combined housing system (PP), and four were housed in a gestation-pen and farrowing-crate combined housing system (PC). Differentially expressed proteins in the colostrum (PP versus CC, and PC versus CC) were screened by proteomics technology, and bioinformatics analysis was then performed. Results showed that 93 proteins were differentially expressed in PP versus CC, and that 126 proteins were differentially expressed in PC versus CC. The differentially expressed proteins in the PP versus CC comparison were mainly enriched in interleukin (IL)-17, transforming growth factor-β, and nuclear factor-κ B signaling pathways, and in metabolic pathways, including glutathione metabolism, peroxisome, and carbon metabolism. In contrast, differentially expressed proteins in the PC versus CC comparison were enriched in the IL-17 signaling pathway, cholesterol metabolism, and peroxisome proliferator-activated receptor signaling pathway. In conclusion, the housing environment appeared to affect the colostrum composition of sows by acting on their immune system and metabolic processes, particularly fat metabolism.

Differential Potential of Phytophthora capsici Resistance Mechanisms to the Fungicide Metalaxyl in Peppers.

Metalaxyl is one of the main fungicides used to control pepper blight caused by Phytophthora capsici. Metalaxyl resistance of P. capsici, caused by the long-term intense use of this fungicide, has become one of the most serious challenges facing pest management. To reveal the potential resistance mechanism of P. capsici to fungicide metalaxyl, a metalaxyl-resistant mutant strain SD1-9 was obtained under laboratory conditions. The pathogenicity test showed that mutant strain SD1-9 had different pathogenicity to different host plants with or without the treatment of metalaxyl compared with that of the wild type SD1. Comparative transcriptome sequencing of mutant strain SD1-9 and wild type SD1 led to the identification of 3845 differentially expressed genes, among them, 517 genes were upregulated, while 3328 genes were down-regulated in SD1-9 compared to that in the SD1. The expression levels of 10 genes were further verified by real-time RT-PCR. KEGG analysis showed that the differentially expressed genes were enriched in the peroxisome, endocytosis, alanine and tyrosine metabolism. The expression of the candidate gene XLOC_020226 during 10 life history stages was further studied, the results showed that expression level reached a maximum at the zoospores stage and basically showed a gradually increasing trend with increasing infection time in pepper leaves in SD1-9 strain, while its expression gradually increased in the SD1 strain throughout the 10 stages, indicated that XLOC_020226 may be related to the growth and pathogenicity of P. capsici. In summary, transcriptome analysis of plant pathogen P. capsici strains with different metalaxyl resistance not only provided database of the genes involved in the metalaxyl resistance of P. capsici, but also allowed us to gain novel insights into the potential resistance mechanism of P. capsici to metalaxyl in peppers.

Developmental and Degenerative Cerebellar Pathologies in Peroxisomal β-Oxidation Deficiency.

The integrity of the cerebellum is exquisitely dependent on peroxisomal β-oxidation metabolism. Patients with peroxisomal β-oxidation defects commonly develop malformation, leukodystrophy, and/or atrophy of the cerebellum depending on the gene defect and on the severity of the mutation. By analyzing mouse models lacking the central peroxisomal β-oxidation enzyme, multifunctional protein-2 (MFP2), either globally or in selected cell types, insights into the pathomechanisms could be obtained. All mouse models developed ataxia, but the onset was earlier in global and neural-selective (Nestin) Mfp2-/- knockout mice as compared to Purkinje cell (PC)-selective Mfp2 knockouts.At the histological level, this was associated with developmental anomalies in global and Nestin-Mfp2-/- mice, including aberrant wiring of PCs by parallel and climbing fibers and altered electrical properties of PCs. In all mouse models, dystrophy of PC axons with swellings initiating in the deep cerebellar nuclei and evolving to the proximal axon, preceded death of PCs. These degenerative features are in part mediated by deficient peroxisomal β-oxidation within PCs but are accelerated when MFP2 is also absent from other neural cell types. The metabolic causes of the diverse cerebellar pathologies remain unknown.In conclusion, peroxisomal β-oxidation is required both for the development and for the maintenance of the cerebellum. This is mediated by PC autonomous and nonautonomous mechanisms.

Peroxisome proliferator-activated receptor gamma (PPARγ) activation and metabolism disturbance induced by bisphenol A and its replacement analog bisphenol S using in vitro macrophages and in vivo mouse models

Bisphenol A (BPA) and its replacement analog, bisphenol S (BPS), have been proposed as environmental obesogen to disrupt the lipid metabolism through regulating peroxisome proliferator-activated receptor gamma (PPARγ) receptor. However, there is a dearth of information on whether this biological effect can occur in human macrophage, a cell type which closely interacts with adipocytes and hepatocytes to control lipid metabolism. Here, we for the first time investigate the activity of BPA and BPS on PPARγ pathway in human macrophages. The results demonstrated that BPA and BPS served as activators of PPARγ in human macrophage cell line, and significantly induced the expression of lipid metabolism-related genes, including fatty acid binding protein 4 (FABP4), cluster of differentiation 36 (CD36) and nuclear receptor subfamily 1 group H member 3 (NR1H3). In PPARγ knockout cells, expression of these genes was down-regulated, suggesting that these genes are dependent on PPARγ. The underlying mechanisms were further investigated using an in vivo mouse model, and the results confirmed the induction of PPARγ and its respective target genes in mice following exposure to BPA or BPS. Moreover, the observed alteration of PPARγ expression highly correlated with the disturbance of metabolism profiles in liver tissues as detected by 1H Nuclear Magnetic Resonance (NMR)-based metabonomics. Overall, this study provided the first evidence that BPA and BPS activated PPARγ and its target genes in human macrophages, and provided comprehensive information to confirm that BPA and BPS disturb the metabolism through targeting PPARγ via both in vitro assays and in vivo animal models.

A Multi-Omics Study of Chicken Infected by Nephropathogenic Infectious Bronchitis Virus.

Chicken gout resulting from nephropathogenic infectious bronchitis virus (NIBV) has become a serious kidney disease problem in chicken worldwide with alterations of the metabolic phenotypes in multiple metabolic pathways. To investigate the mechanisms in chicken responding to NIBV infection, we examined the global transcriptomic and metabolomic profiles of the chicken’s kidney using RNA-seq and GC–TOF/MS, respectively. Furthermore, we analyzed the alterations in cecal microorganism composition in chickens using 16S rRNA-seq. Integrated analysis of these three phenotypic datasets further managed to create correlations between the altered kidney transcriptomes and metabolome, and between kidney metabolome and gut microbiome. We found that 2868 genes and 160 metabolites were deferentially expressed or accumulated in the kidney during NIBV infection processes. These genes and metabolites were linked to NIBV-infection related processes, including immune response, signal transduction, peroxisome, purine, and amino acid metabolism. In addition, the comprehensive correlations between the kidney metabolome and cecal microbial community showed contributions of gut microbiota in the progression of NIBV-infection. Taken together, our research comprehensively describes the host responses during NIBV infection and provides new clues for further dissection of specific gene functions, metabolite affections, and the role of gut microbiota during chicken gout.

Benchmarking two Saccharomyces cerevisiae laboratory strains for growth and transcriptional response to methanol

One-carbon compounds, such as methanol, are becoming potential alternatives to sugars as feedstocks for the biological production of chemicals, fuels, foods, and pharmaceuticals. Efficient biological production often requires extensive genetic manipulation of a microbial host strain, making well-characterised and genetically-tractable model organisms like the yeast Saccharomyces cerevisiae attractive targets for the engineering of methylotrophic metabolism. S. cerevisiae strains S288C and CEN.PK are the two best-characterised and most widely used hosts for yeast synthetic biology and metabolic engineering, yet they have unpredictable metabolic phenotypes related to their many genomic differences. We therefore sought to benchmark these two strains as potential hosts for engineered methylotrophic metabolism by comparing their growth and transcriptomic responses to methanol. CEN.PK had improved growth in the presence of methanol relative to the S288C derivative BY4741. The CEN.PK transcriptome also had a specific and relevant response to methanol that was either absent or less pronounced in the BY4741 strain. This response included up-regulation of genes associated with mitochondrial and peroxisomal metabolism, alcohol and formate dehydrogenation, glutathione metabolism, and the global transcriptional regulator of metabolism MIG3. Over-expression of MIG3 enabled improved growth in the presence of methanol, suggesting that MIG3 is a mediator of the superior CEN.PK strain growth. CEN.PK was therefore identified as a superior strain for the future development of synthetic methylotrophy in S. cerevisiae.

Autophagic Machinery of Plant Peroxisomes.

Peroxisomes are cell organelles that play an important role in plants in many physiological and developmental processes. The plant peroxisomes harbor enzymes of the β-oxidation of fatty acids and the glyoxylate cycle; photorespiration; detoxification of reactive oxygen and nitrogen species; as well as biosynthesis of hormones and signal molecules. The function of peroxisomes in plant cells changes during plant growth and development. They are transformed from organelles involved in storage lipid breakdown during seed germination and seedling growth into leaf peroxisomes involved in photorespiration in green parts of the plant. Additionally, intensive oxidative metabolism of peroxisomes causes damage to their components. Therefore, unnecessary or damaged peroxisomes are degraded by selective autophagy, called pexophagy. This is an important element of the quality control system of peroxisomes in plant cells. Despite the fact that the mechanism of pexophagy has already been described for yeasts and mammals, the molecular mechanisms by which plant cells recognize peroxisomes that will be degraded via pexophagy still remain unclear. It seems that a plant-specific mechanism exists for the selective degradation of peroxisomes. In this review, we describe the physiological role of pexophagy in plant cells and the current hypotheses concerning the mechanism of plant pexophagy.

Covering the Cover

Covering the Cover

Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease.

Hydrogen peroxide (H2O2), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipid metabolism, also serve as hubs in the H2O2 signaling network. We first briefly introduce the basic concepts of how H2O2 can drive cellular signaling events. Next, we outline the peroxisomal enzyme systems involved in H2O2 metabolism in mammals and reflect on how this oxidant can permeate across the organellar membrane. In addition, we provide an up-to-date overview of molecular targets and biological processes that can be affected by changes in peroxisomal H2O2 metabolism. Where possible, emphasis is placed on the molecular mechanisms and factors involved. From the data presented, it is clear that there are still numerous gaps in our knowledge. Therefore, gaining more insight into how peroxisomes are integrated in the cellular H2O2 signaling network is of key importance to unravel the precise role of peroxisomal H2O2 production and scavenging in normal and pathological conditions.