BBA - Molecular Basis of Disease (v.1822, #9)

Metabolic functions and biogenesis of peroxisomes in health and disease by Hans R. Waterham; Ronald J.A. Wanders (1325).

Molecular basis of peroxisomal biogenesis disorders caused by defects in peroxisomal matrix protein import by Shirisha Nagotu; Vishal C. Kalel; Ralf Erdmann; Harald W. Platta (1326-1336).
Peroxisomal biogenesis disorders (PBDs) represent a spectrum of autosomal recessive metabolic disorders that are collectively characterized by abnormal peroxisome assembly and impaired peroxisomal function. The importance of this ubiquitous organelle for human health is highlighted by the fact that PBDs are multisystemic disorders that often cause death in early infancy. Peroxisomes contribute to central metabolic pathways. Most enzymes in the peroxisomal matrix are linked to lipid metabolism and detoxification of reactive oxygen species. Proper assembly of peroxisomes and thus also import of their enzymes relies on specific peroxisomal biogenesis factors, so called peroxins with PEX being the gene acronym. To date, 13 PEX genes are known to cause PBDs when mutated. Studies of the cellular and molecular defects in cells derived from PBD patients have significantly contributed to the understanding of the functional role of the corresponding peroxins in peroxisome assembly. In this review, we discuss recent data derived from both human cell culture as well as model organisms like yeasts and present an overview on the molecular mechanism underlying peroxisomal biogenesis disorders with emphasis on disorders caused by defects in the peroxisomal matrix protein import machinery. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► Peroxisomal Biogenesis Disorders (PBD) are severe metabolic diseases. ► Most PBDs are caused by defects in peroxisomal matrix protein import. ► The principles of matrix protein import are conserved from yeast to man. ► We discuss a unified model based on data derived from patients and model organisms.
Keywords: Peroxisome biogenesis disorders; Zellweger syndrome spectrum; PEX; Peroxin; Ubiquitination;

Peroxisome biogenesis disorders: Molecular basis for impaired peroxisomal membrane assembly by Yukio Fujiki; Yuichi Yagita; Takashi Matsuzaki (1337-1342).
Peroxisome is a single-membrane organelle in eukaryotes. The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome (ZS). Gene defects of peroxins required for both membrane assembly and matrix protein import are identified: ten mammalian pathogenic peroxins for ten complementation groups of PBDs, are required for matrix protein import; three, Pex3p, Pex16p and Pex19p, are shown to be essential for peroxisome membrane assembly and responsible for the most severe ZS in PBDs of three complementation groups 12, 9, and 14, respectively. Patients with severe ZS with defects of PEX3, PEX16, and PEX19 tend to carry severe mutation such as nonsense mutations, frameshifts and deletions. With respect to the function of these three peroxins in membrane biogenesis, two distinct pathways have been proposed for the import of peroxisomal membrane proteins in mammalian cells: a Pex19p- and Pex3p-dependent class I pathway and a Pex19p- and Pex16p-dependent class II pathway. In class II pathway, Pex19p also forms a soluble complex with newly synthesized Pex3p as the chaperone for Pex3p in the cytosol and directly translocates it to peroxisomes. Pex16p functions as the peroxisomal membrane receptor that is specific to the Pex3p-Pex19p complexes. A model for the import of peroxisomal membrane proteins is suggested, providing new insights into the molecular mechanisms underlying the biogenesis of peroxisomes and its regulation involving Pex3p, Pex19p, and Pex16p. Another model suggests that in Saccharomyces cerevisiae peroxisomes likely emerge from the endoplasmic reticulum. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.► Peroxisomal Biogenesis Disorders (PBDs) are autosomal recessive metabolic diseases. ► PBDs are caused by defects in peroxisomal import of membrane and/or matrix proteins. ► Peroxins essential for peroxisome membrane assembly are Pex3p, Pex16p, and Pex19p. ► We address a model based on data from CHO mutants and cells from patients with PBDs.
Keywords: Peroxisome biogenesis disorder; Membrane biogenesis; Peroxin; CHO cell mutant; Membrane protein transporter; Classes I and II import pathway;

Fission and proliferation of peroxisomes by M. Schrader; N.A. Bonekamp; M. Islinger (1343-1357).
Peroxisomes are remarkably dynamic, multifunctional organelles, which react to physiological changes in their cellular environment and adopt their morphology, number, enzyme content and metabolic functions accordingly. At the organelle level, the key molecular machinery controlling peroxisomal membrane elongation and remodeling as well as membrane fission is becoming increasingly established and defined. Key players in peroxisome division are conserved in animals, plants and fungi, and key fission components are shared with mitochondria. However, the physiological stimuli and corresponding signal transduction pathways regulating and modulating peroxisome maintenance and proliferation are, despite a few exceptions, largely unexplored. There is emerging evidence that peroxisomal dynamics and proper regulation of peroxisome number and morphology are crucial for the physiology of the cell, as well as for the pathology of the organism. Here, we discuss several key aspects of peroxisomal fission and proliferation and highlight their association with certain diseases. We address signaling and transcriptional events resulting in peroxisome proliferation, and focus on novel findings concerning the key division components and their interplay. Finally, we present an updated model of peroxisomal growth and division. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► New transcription factors involved in peroxisome proliferation have been discovered. ► Pex11p bends peroxisomal membranes via insertion of an amphipathic helix. ► Peroxisome division follows a multistep maturation pathway and is an asymmetric process. ► Peroxisomes and mitochondria share key components of their fission machinery. ► In mammals, Mff is the main DLP1-recruiting receptor at peroxisomal and mitochondrial membranes.
Keywords: Peroxisome proliferation; Organelle dynamics; DLP1/DRP1; FIS1; Mff; Pex11;

Peroxisomes, cell senescence, and rates of aging by Courtney R. Giordano; Stanley R. Terlecky (1358-1362).
The peroxisome is functionally integrated into an exquisitely complex network of communicating endomembranes which is only beginning to be appreciated. Despite great advances in identifying essential components and characterizing molecular mechanisms associated with the organelle's biogenesis and function, there is a large gap in our understanding of how peroxisomes are incorporated into metabolic pathways and subcellular communication networks, how they contribute to cellular aging, and where their influence is manifested on the initiation and progression of degenerative disease. In this review, we summarize recent evidence pointing to the organelle as an important regulator of cellular redox balance with potentially far-reaching effects on cell aging and the genesis of human disease. The roles of the organelle in lipid homeostasis, anaplerotic reactions, and other critical metabolic and biochemical processes are addressed elsewhere in this volume. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► Peroxisomes synthesize and degrade reactive oxygen species. ► Catalase is a critical antioxidant enzyme with a major role in cell and organismal aging. ► Supplementation of cellular catalase may impact lifespan and alter the course of degenerative disease. ► Peroxisome function and redox balance are tied to rates of aging.
Keywords: Peroxisome; Senescence; Aging; Catalase; Reactive oxygen species; Degenerative disease;

Role of peroxisomes in ROS/RNS-metabolism: Implications for human disease by Marc Fransen; Marcus Nordgren; Bo Wang; Oksana Apanasets (1363-1373).
Peroxisomes are cell organelles that play a central role in lipid metabolism. At the same time, these organelles generate reactive oxygen and nitrogen species as byproducts. Peroxisomes also possess intricate protective mechanisms to counteract oxidative stress and maintain redox balance. An imbalance between peroxisomal reactive oxygen species/reactive nitrogen species production and removal may possibly damage biomolecules, perturb cellular thiol levels, and deregulate cellular signaling pathways implicated in a variety of human diseases. Somewhat surprisingly, the potential role of peroxisomes in cellular redox metabolism has been underestimated for a long time. However, in recent years, peroxisomal reactive oxygen species/reactive nitrogen species metabolism and signaling have become the focus of a rapidly evolving and multidisciplinary research field with great prospects. This review is mainly devoted to discuss evidence supporting the notion that peroxisomal metabolism and oxidative stress are intimately interconnected and associated with age-related diseases. We focus on several key aspects of how peroxisomes contribute to cellular reactive oxygen species/reactive nitrogen species levels in mammalian cells and how these cells cope with peroxisome-derived oxidative stress. We also provide a brief overview of recent strategies that have been successfully employed to detect and modulate the peroxisomal redox status. Finally, we highlight some gaps in our knowledge and propose potential avenues for further research. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.Schematic overview of the potential sources, sinks, and targets of peroxisomal ROS/RNS. Peroxisomes contain various enzymes that produce hydrogen peroxide (H2O2), superoxide (O2), or nitric oxide (NO•) as part of their normal catalytic cycle. These molecules can readily react to form other ROS and RNS such as peroxynitrite (ONOO), hydroxyl radical (•OH), and alkyl peroxides (ROOH). Peroxisomes are also well equipped with enzymatic and non ezymatic antioxidant defense systems, including catalase (CAT), superoxide dismutase 1 (SOD1), peroxiredoxin 5 (PRDX5), glutathione S‐transferase kappa (GSTK1), ‘microsomal’ glutathione S‐transferase (MGST1), epoxide hydrolase 2 (EPHX2), reduced glutathione (GSH) and vitamin C (VitC). GSH and VitC most likely freely penetrate the peroxisomal membrane through PXMP2, a non‐selective pore‐forming protein with an upper molecular size limit of 300–600 Da. How oxidized glutathione (GSSG) is reduced inside the peroxisomal matrix or exported back into the cytosol, is not yet known. The precise substrates of GSTK1, MGST1, and EPHX2 also remain to be identified. Excess peroxisomal ROS/RNS can directly inactivate peroxisomal matrix proteins or promote the production of potential signaling molecules such as S‐nitrosoglutathione (GSNO). Alternatively, some of these small reactive molecules may induce membrane damage through lipid peroxidation or diffuse out of the organelle. The latter event may perturb the cellular redox status, a condition generally considered as a risk factor for the development of age‐related diseases. Finally, under conditions of increased oxidative stress, peroxisomes may also function as a sink for cellular ROS. However, such conditions may in turn affect various peroxisomal functions, including the PEX‐mediated import pathway of peroxisomal matrix protein. XDH, xanthine oxidase; NOS2, inducible nitric oxide synthase; GRX, glutaredoxin; ROH, alcohol; ONO, nitrite.Display Omitted► Peroxisomes may function as a source, sink, or target of small reactive molecules. ► Peroxisomal ROS/RNS can deregulate redox-sensitive signaling pathways. ► Peroxisomes and mitochondria share a redox-sensitive relationship. ► Altered peroxisomal redox homeostasis is linked with age-associated diseases. ► Enhanced cellular oxidative stress can impair peroxisome function.
Keywords: Peroxisome; Oxidative stress; Antioxidant; Redox signaling; Interorganellar crosstalk; Age-related disease;

Transfer of metabolites across the peroxisomal membrane by Vasily D. Antonenkov; J. Kalervo Hiltunen (1374-1386).
Peroxisomes perform a large variety of metabolic functions that require a constant flow of metabolites across the membranes of these organelles. Over the last few years it has become clear that the transport machinery of the peroxisomal membrane is a unique biological entity since it includes nonselective channels conducting small solutes side by side with transporters for ‘bulky’ solutes such as ATP. Electrophysiological experiments revealed several channel-forming activities in preparations of plant, mammalian, and yeast peroxisomes and in glycosomes of Trypanosoma brucei. The properties of the first discovered peroxisomal membrane channel – mammalian Pxmp2 protein – have also been characterized. The channels are apparently involved in the formation of peroxisomal shuttle systems and in the transmembrane transfer of various water-soluble metabolites including products of peroxisomal β-oxidation. These products are processed by a large set of peroxisomal enzymes including carnitine acyltransferases, enzymes involved in the synthesis of ketone bodies, thioesterases, and others. This review discusses recent data pertaining to solute permeability and metabolite transport systems in peroxisomal membranes and also addresses mechanisms responsible for the transfer of ATP and cofactors such as an ATP transporter and nudix hydrolases. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► We describe transport of solutes across the peroxisomal membrane. ► The membrane contains pore-forming channels and transporters for ATP. ► Export from peroxisomes of the beta-oxidation products is described. ► Transfer of cofactors across the membrane is analyzed.
Keywords: Peroxisome; Membrane transport; Channel; Transporter; Pxmp2 protein;

Peroxisomal ABC transporters: Structure, function and role in disease by Masashi Morita; Tsuneo Imanaka (1387-1396).
ATP-binding cassette (ABC) transporters belong to one of the largest families of membrane proteins, and are present in almost all living organisms from eubacteria to mammals. They exist on plasma membranes and intracellular compartments such as the mitochondria, peroxisomes, endoplasmic reticulum, Golgi apparatus and lysosomes, and mediate the active transport of a wide variety of substrates in a variety of different cellular processes. These include the transport of amino acids, polysaccharides, peptides, lipids and xenobiotics, including drugs and toxins. Three ABC transporters belonging to subfamily D have been identified in mammalian peroxisomes. The ABC transporters are half-size and assemble mostly as a homodimer after posttranslational transport to peroxisomal membranes. ABCD1/ALDP and ABCD2/ALDRP are suggested to be involved in the transport of very long chain acyl-CoA with differences in substrate specificity, and ABCD3/PMP70 is involved in the transport of long and branched chain acyl-CoA. ABCD1 is known to be responsible for X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation of very long chain fatty acids. Here, we summarize recent advances and important points in our advancing understanding of how these ABC transporters target and assemble to peroxisomal membranes and perform their functions in physiological and pathological processes, including the neurodegenerative disease, X-ALD. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► Peroxisomal ABC transporters (ABCD1–3) are half-size and assemble mostly as a homodimer. ► Peroxisomal ABC transporters are posttranslationally transported to peroxisomal membranes. ► Peroxisomal ABC transporters are involved in the transport of a variety of acyl-CoAs. ► Dysfunction of ABCD1 causes X-linked adrenoleukodystrophy, a neurodegenerative disorder. ► ABCD1 and 2 are responsible for axonal integrity and myelination in central nervous system.
Keywords: ABC transporter; Acyl-CoA transport; Adrenoleukodystrophy; Fatty acid β-oxidation; Peroxisome targeting;

The importance of peroxisomes in lipid metabolism is now well established and peroxisomes contain approximately 60 enzymes involved in these lipid metabolic pathways. Several acyl-CoA thioesterase enzymes (ACOTs) have been identified in peroxisomes that catalyze the hydrolysis of acyl-CoAs (short-, medium-, long- and very long-chain), bile acid-CoAs, and methyl branched-CoAs, to the free fatty acid and coenzyme A. A number of acyltransferase enzymes, which are structurally and functionally related to ACOTs, have also been identified in peroxisomes, which conjugate (or amidate) bile acid-CoAs and acyl-CoAs to amino acids, resulting in the production of amidated bile acids and fatty acids. The function of ACOTs is to act as auxiliary enzymes in the α- and β-oxidation of various lipids in peroxisomes. Human peroxisomes contain at least two ACOTs (ACOT4 and ACOT8) whereas mouse peroxisomes contain six ACOTs (ACOT3, 4, 5, 6, 8 and 12). Similarly, human peroxisomes contain one bile acid-CoA:amino acid N-acyltransferase (BAAT), whereas mouse peroxisomes contain three acyltransferases (BAAT and acyl-CoA:amino acid N-acyltransferases 1 and 2: ACNAT1 and ACNAT2). This review will focus on the human and mouse peroxisomal ACOT and acyltransferase enzymes identified to date and discuss their cellular localizations, emerging structural information and functions as auxiliary enzymes in peroxisomal metabolic pathways. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► ACOTs regulate acyl-CoA metabolism in peroxisomes. ► Peroxisomes produce glycine and taurine-conjugated fatty acids. ► BAAT is involved in the inheritance of familial hypercholanemia. ► New insights into acyl-CoA thioesterase structure and function. ► ACOTs structurally belong to the α/β hydrolase and HotDog fold protein superfamilies.
Keywords: Acyl-CoA thioesterase; Peroxisome; Bile acid-CoA:amino acid N-acyltransferase; N-Acyl taurine; Coenzyme A; Protein structure;

Peroxisomal acyl-CoA synthetases by Paul A. Watkins; Jessica M. Ellis (1411-1420).
Peroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group—either a fatty acid or the acyl side chain of a steroid derivative—be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or “activation”, reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal acyl-CoA synthetases that participate in these pathways. Of the 26 acyl-CoA synthetases encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, SLC27A2, and SLC27A4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of acyl-CoA synthetases in peroxisomes, much of which was obtained before the existence of multiple acyl-CoA synthetase isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific acyl-CoA synthetase isoforms in lipid metabolism. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► Peroxisomes carry out several metabolic processes requiring activated fatty acids (acyl-CoAs). ► Acyl-CoA synthetases catalyze the formation of activated fatty acids. ► Peroxisomes have acyl-CoA synthetase activity, but only three of the 26 mammalian enzymes have been detected in peroxisomes. ► This article summarizes the current state of knowledge of peroxisomal acyl-CoA synthetase function.
Keywords: Peroxisome; Acyl-CoA synthetase; Lipid metabolism; Fatty acid activation;

Peroxisomal disorders are an important group of neurometabolic diseases. The clinical presentation is varied in terms of age of onset, severity, and different neurological symptoms. The clinical course spans from death in infancy, rapid functional decline, slow decline on long-term followup, to apparent stable course. Leukoencephalopathy and developmental anomalies are characteristic findings on cerebral MR imaging. From a diagnostic point of view the disorders can be clinically subdivided into four broad categories: (1) the Zellweger spectrum disorders and the peroxisomal ß-oxidation disorders, (2) the rhizomelic chondrodysplasia punctata spectrum disorders, (3) the X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex and (4) the remaining disorders. This article discusses the role of MRI findings in the clinical approach of peroxisomal disorders with neurological disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.► Clinical courses of peroxisomal disorders spans from death in infancy to stable course. ► MRI studies may identify leukoencephalopathy and developmental anomalies. ► MRI patterns can be used in the clinical approach of peroxisomal disorders.
Keywords: Peroxisomal disorder; Zellweger spectrum disorder; Peroxisomal acyl-CoA oxidase deficiency; D-bifunctional protein deficiency; X-linked adrenoleukodystrophy; Rhizomelic chondrodysplasia punctata;

Genetics and molecular basis of human peroxisome biogenesis disorders by Hans R. Waterham; Merel S. Ebberink (1430-1441).
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. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.► Peroxisome biogenesis disorders (PBDs) are clinically, biochemically and genetically heterogeneous. ► PBDs are autosomal recessive disorders which can be caused by any of at least 14 different PEX genes. ► PEX genes encode proteins involved in peroxisome assembly, including protein import and peroxisome division. ► Genetic testing for all PEX genes is available as diagnostic service.
Keywords: Peroxisome biogenesis disorder; Zellweger syndrome spectrum; PEX genes; Peroxisome assembly; Genetic testing;

Functions of plasmalogen lipids in health and disease by Nancy E. Braverman; Ann B. Moser (1442-1452).
Plasmalogens are a unique class of membrane glycerophospholipids containing a fatty alcohol with a vinyl-ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone. These two features provide novel properties to these compounds. Although plasmalogens represent up to 20% of the total phospholipid mass in humans their physiological roles have been challenging to identify, and are likely to be particular to different tissues, metabolic processes and developmental stages. Their biosynthesis starts in peroxisomes, and defects at these steps cause the malformation syndrome, Rhizomelic Chondrodysplasia Punctata (RCDP). The RCDP phenotype predicts developmental roles for plasmalogens in bone, brain, lens, lung, kidney and heart. Recent studies have revealed secondary plasmalogen deficiencies associated with more common disorders and allow us to tease out additional pathways dependent on plasmalogen functions. In this review, we present current knowledge of plasmalogen biology in health and disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.► Plasmalogen synthesis and regulation. ► Unique roles ascribed to these molecules: anti-oxidants, membrane structure, signal transduction. ► Primary plasmalogen deficiency disease states: RCDP. ► Secondary plasmalogen deficiency disease states: respiratory disorders, Alzheimer disease. ► Plasmalogen replacement therapy.
Keywords: Plasmalogen; Rhizomelic Chondrodysplasia Punctata; Alzheimer disease; Respiratory disease; Lipid signaling; Plasmalogen replacement therapy;

Primary hyperoxalurias: Disorders of glyoxylate detoxification by Eduardo Salido; Angel L. Pey; Rosa Rodriguez; Victor Lorenzo (1453-1464).
Glyoxylate detoxification is an important function of human peroxisomes. Glyoxylate is a highly reactive molecule, generated in the intermediary metabolism of glycine, hydroxyproline and glycolate mainly. Glyoxylate accumulation in the cytosol is readily transformed by lactate dehydrogenase into oxalate, a dicarboxylic acid that cannot be metabolized by mammals and forms tissue-damaging calcium oxalate crystals. Alanine-glyoxylate aminotransferase, a peroxisomal enzyme in humans, converts glyoxylate into glycine, playing a central role in glyoxylate detoxification. Cytosolic and mitochondrial glyoxylate reductase also contributes to limit oxalate production from glyoxylate. Mitochondrial hydroxyoxoglutarate aldolase is an important enzyme of hydroxyproline metabolism. Genetic defect of any of these enzymes of glyoxylate metabolism results in primary hyperoxalurias, severe human diseases in which toxic levels of oxalate are produced by the liver, resulting in progressive renal damage. Significant advances in the pathophysiology of primary hyperoxalurias have led to better diagnosis and treatment of these patients, but current treatment relies mainly on organ transplantation. It is reasonable to expect that recent advances in the understanding of the molecular mechanisms of disease will result into better targeted therapeutic options in the future. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.► Errors of glyoxylate detoxification result in primary hyperoxalurias. ► Molecular genetics of primary hyperoxalurias are reviewed. ► Main clinical aspects of primary hyperoxalurias are summarized. ► Prospects for molecular therapies are discussed.
Keywords: Primary hyperoxaluria; Oxalate; Glyoxylate; AGXT; GRHPR; HOGA1;

X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects by Stephan Kemp; Johannes Berger; Patrick Aubourg (1465-1474).
X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by the age of 60 years. Mutations in the ABCD1 gene affect the function of the encoded protein ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients have mutations in the ABCD1 gene, there is no general genotype–phenotype correlation. Environmental factors and a multitude of modifying genes appear to determine the clinical manifestation in this monogenetic but multifactorial disease. This review focuses on the clinical, biochemical, genetic and pathophysiological aspects of X-ALD. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► We review X-linked adrenoleukodystrophy (X-ALD), the most common leukodystrophy. ► We describe the clinical presentations of X-ALD. ► We discuss the biochemical background and the pathogenesis of X-ALD. ► Potential pitfalls in diagnosis are reviewed.
Keywords: ALDP; ELOVL1; Peroxisome; VLCFA; Leukodystrophy; ABCD1;

Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases? by Elena Galea; Nathalie Launay; Manuel Portero-Otin; Montserrat Ruiz; Reinald Pamplona; Patrick Aubourg; Isidre Ferrer; Aurora Pujol (1475-1488).
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder expressed as four disease variants characterized by adrenal insufficiency and graded damage in the nervous system. X-ALD is caused by a loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long chain fatty acids (VLCFA) in the organs and plasma, which have potentially toxic effects in CNS and adrenal glands. We have recently shown that treatment with a combination of antioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage and energetic failure, together with the axonal degeneration and locomotor impairment displayed by Abcd1 null mice, the animal model of X-ALD. This is the first direct demonstration that oxidative stress, which is a hallmark not only of X-ALD, but also of other neurodegenerative processes, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), contributes to axonal damage. The purpose of this review is, first, to discuss the molecular and cellular underpinnings of VLCFA-induced oxidative stress, and how it interacts with energy metabolism and/or inflammation to generate a complex syndrome wherein multiple factors are contributing. Particular attention will be paid to the dysregulation of redox homeostasis by the interplay between peroxisomes and mitochondria. Second, we will extend this analysis to the aforementioned neurodegenerative diseases with the aim of defining differences as well as the existence of a core pathogenic mechanism that would justify the exchange of therapeutic opportunities among these pathologies. This article is part of a Special Issue entitled: Metabolic functions and biogenesis of peroxisomes in health and disease.► Oxidative and metabolic damage contribute to axonal degeneration in X-ALD. ► We underscore the commonalities between X-ALD and major neurodegenerative diseases. ► We focus on therapeutic approaches against oxidative damage for X-ALD.
Keywords: Oxidative stress; Neurodegenerative disease; Adrenoleukodystrophy; Metabolic failure; Mitochondria; Fatty acid;

Peroxisome biogenesis and peroxisomal β-oxidation defects are rare inherited metabolic disorders in which several organs can be affected. A panel of mouse models has been created in which genes crucial to these processes were inactivated and the ensuing pathologies studied. In mice with enzyme defects of peroxisomal β-oxidation, the disease state strongly depends on the kind of substrates that are metabolized by the enzyme and the dietary composition. Because mice with generalized biogenesis defects seldom reach adulthood, conditional knockout models were generated to study the consequences of peroxisome deficiency in hepatocytes, different brain cell types and Sertoli cells. Although the precise relationship between the biochemical anomalies and pathologies was often not resolved, the mouse models allowed to document in detail histological abnormalities, metabolic and gene expression deregulations some of which are mediated by PPARα, and to uncover the essential role of peroxisomes in some unsuspected cell types. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.►Inactivity of peroxisomal β-oxidation enzymes in mouse liver causes PPARα activation and metabolic deregulation. ►Complete loss of peroxisome function in hepatocytes impacts on mitochondria, energy homeostasis and ER. ►Peroxisomes and peroxisomal β-oxidation are necessary for male fertility and brain integrity. ►The mouse models recapitulate pathologies of patients with peroxisome biogenesis or β-oxidation defects.
Keywords: Peroxisome; Conditional knockout; neurodegeneration; PPARalpha; VLCFA; Bile acids;

The importance of ether-phospholipids: A view from the perspective of mouse models by Tiago Ferreira da Silva; Vera F. Sousa; Ana R. Malheiro; Pedro Brites (1501-1508).
Ether-phospholipids represent an important group of phospholipids characterized by an alkyl or an alkenyl bond at the sn-1 position of the glycerol backbone. Plasmalogens are the most abundant form of alkenyl-glycerophospholipids, and their synthesis requires functional peroxisomes. Defects in the biosynthesis of plasmalogens are the biochemical hallmark of the human peroxisomal disorder Rhizomelic Chondrodysplasia Punctata (RCDP), which is characterized by defects in eye, bone and nervous tissue. The generation and characterization of mouse models with defects in plasmalogen levels have significantly advanced our understanding of the role and importance of plasmalogens as well as pathogenetic mechanisms underlying RCDP. A review of the current mouse models and the description of the combined knowledge gathered from the histopathological and biochemical studies is presented and discussed. Further characterization of the role and functions of plasmalogens will contribute to the elucidation of disease pathogenesis in peroxisomal and non-peroxisomal disorders. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.► Plasmalogens are a special subclass of phospholipids containing a vinyl-ether bond. ► A deficiency in plasmalogens affects multiple tissues and a myriad of human disorders. ► Several mouse mutants have been generated to serve as models for human disorders. ► There is a good correlation between the human disorders and the mouse mutants. ► Plasmalogen loss may modulate tissue pathology in several neurologic disorders.
Keywords: Plasmalogen; Peroxisome; Nervous tissue; Oxidative stress; Knockout; Disease mechanism;