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The Role of Peroxisome in Cell Functions and Pathological Consequences...
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The Role of Peroxisome in Cell Functions and Pathological Consequences of Its Dysfunction

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 11406

Special Issue Editors

Prof. Dr. Mustapha Cherkaoui-Malki

E-Mail Website
Guest Editor
Laboratoire BioPeroxIL (Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique), EA 7270, Université de Bourgogne-Franche Comté, F-21000 Dijon, France
Interests: lipid metabolism and peroxisomal functions
Dr. Pierre Andreoletti

E-Mail Website
Guest Editor
Bio-PeroxIL Laboratory, Université Bourgogne Franche-Comté, Dijon, France
Interests: lipid metabolism and peroxisomal functions

Special Issue Information

Dear Colleagues,

Over the last ten years, more than seventy thousand citations were recorded in the peroxisome field. The covered areas include Biochemistry Molecular Biology, Cell Biology, Plant Sciences, Genetics Heredity, Microbiology, Biotechnology, Medicine Research Experimental and Endocrinology-Metabolism, among others. Indeed, peroxisome became fashionable due to its incredible capacity in exhibiting, across different species, different functions by adapting its proteinaceous arsenal and permitting cells to face unpredictable environmental conditions. The downside to one or several peroxisomal functions is that it has a deleterious impact on cell homeostasis and organism survival, highlighted particularly by several human peroxisome disorders.

This Special Issue aims to offer a compendium of research, including the last experiments and the scaffolded hypothesis on the role of peroxisome in cell functions and the implication of this unique cell compartment in different metabolic pathways and cell signaling, highlighting its dynamic biology that can be seen under physiological and/or pathological conditions.

Prof. Dr. Mustapha Cherkaoui-Malki
Dr. Pierre Andreoletti
Guest Editors

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Keywords

  • biogenesis
  • metabolic pathways
  • cell signaling
  • lipid metabolism
  • β-oxidation
  • peroxin
  • peroxisomal diseases
  • oxidative stress
  • transporters

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Published Papers (4 papers)

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Research

18 pages, 17688 KiB  
Article
Peroxisomal Localization of a Truncated HMG-CoA Reductase under Low Cholesterol Conditions
by Jianqiu Wang, Markus Kunze, Andrea Villoria-González, Isabelle Weinhofer and Johannes Berger
Biomolecules 2024, 14(2), 244; https://doi.org/10.3390/biom14020244 - 19 Feb 2024
Cited by 2 | Viewed by 2390
Abstract
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR [...] Read more.
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR antibodies, we present evidence for a dual localization of HMGCR in the ER and peroxisomes in differentiated human monocytic THP-1 cells, primary human monocyte-derived macrophages and human primary skin fibroblasts under conditions of low cholesterol and statin treatment. Using density gradient centrifugation and Western blot analysis, we observed a truncated HMGCR variant of 76 kDa in the peroxisomal fractions, while a full-length HMGCR of 96 kDa was contained in fractions of the ER. In contrast to primary human control fibroblasts, peroxisomal HMGCR was not found in fibroblasts from patients suffering from type-1 rhizomelic chondrodysplasia punctata, who lack functional PEX7 and, thus, cannot import peroxisomal matrix proteins harboring a type-2 peroxisomal targeting signal (PTS2). Moreover, in the N–terminal region of the soluble 76 kDa C-terminal catalytic domain, we identified a PTS2-like motif, which was functional in a reporter context. We propose that under sterol-depleted conditions, part of the soluble HMGCR domain, which is released from the ER by proteolytic processing for further turnover, remains sufficiently long in the cytosol for peroxisomal import via a PTS2/PEX7-dependent mechanism. Altogether, our findings describe a dual localization of HMGCR under combined lipid depletion and statin treatment, adding another puzzle piece to the complex regulation of HMGCR. Full article
(This article belongs to the Special Issue The Role of Peroxisome in Cell Functions and Pathological Consequences of Its Dysfunction)
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21 pages, 3421 KiB  
Article
Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders
by Andrea Villoria-González, Bettina Zierfuss, Patricia Parzer, Elisabeth Heuböck, Violetta Zujovic, Petra Waidhofer-Söllner, Markus Ponleitner, Paulus Rommer, Jens Göpfert, Sonja Forss-Petter, Johannes Berger and Isabelle Weinhofer
Biomolecules 2023, 13(12), 1696; https://doi.org/10.3390/biom13121696 - 23 Nov 2023
Cited by 4 | Viewed by 2484
Abstract
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary [...] Read more.
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation. Full article
(This article belongs to the Special Issue The Role of Peroxisome in Cell Functions and Pathological Consequences of Its Dysfunction)
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22 pages, 26292 KiB  
Article
ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis
by Agnieszka Buda, Sonja Forss-Petter, Rong Hua, Yorrick Jaspers, Mark Lassnig, Petra Waidhofer-Söllner, Stephan Kemp, Peter Kim, Isabelle Weinhofer and Johannes Berger
Biomolecules 2023, 13(9), 1333; https://doi.org/10.3390/biom13091333 - 31 Aug 2023
Cited by 5 | Viewed by 3318
Abstract
X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, [...] Read more.
X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD. Full article
(This article belongs to the Special Issue The Role of Peroxisome in Cell Functions and Pathological Consequences of Its Dysfunction)
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17 pages, 2326 KiB  
Article
Peroxisomal NAD(H) Homeostasis in the Yeast Debaryomyces hansenii Depends on Two Redox Shuttles and the NAD+ Carrier, Pmp47
by Selva Turkolmez, Serhii Chornyi, Sondos Alhajouj, Lodewijk IJlst, Hans R. Waterham, Phil J. Mitchell, Ewald H. Hettema and Carlo W. T. van Roermund
Biomolecules 2023, 13(9), 1294; https://doi.org/10.3390/biom13091294 - 24 Aug 2023
Cited by 4 | Viewed by 2401
Abstract
Debaryomyces hansenii is considered an unconventional yeast with a strong biotechnological potential, which can produce and store high amounts of lipids. However, relatively little is known about its lipid metabolism, and genetic tools for this yeast have been limited. The aim of this [...] Read more.
Debaryomyces hansenii is considered an unconventional yeast with a strong biotechnological potential, which can produce and store high amounts of lipids. However, relatively little is known about its lipid metabolism, and genetic tools for this yeast have been limited. The aim of this study was to explore the fatty acid β-oxidation pathway in D. hansenii. To this end, we employed recently developed methods to generate multiple gene deletions and tag open reading frames with GFP in their chromosomal context in this yeast. We found that, similar as in other yeasts, the β-oxidation of fatty acids in D. hansenii was restricted to peroxisomes. We report a series of experiments in D. hansenii and the well-studied yeast Saccharomyces cerevisiae that show that the homeostasis of NAD+ in D. hansenii peroxisomes is dependent upon the peroxisomal membrane protein Pmp47 and two peroxisomal dehydrogenases, Mdh3 and Gpd1, which both export reducing equivalents produced during β-oxidation to the cytosol. Pmp47 is the first identified NAD+ carrier in yeast peroxisomes. Full article
(This article belongs to the Special Issue The Role of Peroxisome in Cell Functions and Pathological Consequences of Its Dysfunction)
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