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.
The innate immune response is critical for animal homeostasis and is conserved from invertebrates to vertebrates. This response depends on specialized cells that recognize, internalize, and destroy ...microbial invaders through phagocytosis. This is coupled to autonomous or non-autonomous cellular signaling via reactive oxygen species (ROS) and cytokine production. Lipids are known signaling factors in this process, as the acute phase response of macrophages is accompanied by systemic lipid changes that help resolve inflammation. We found that peroxisomes, membrane-enclosed organelles central to lipid metabolism and ROS turnover, were necessary for the engulfment of bacteria by Drosophila and mouse macrophages. Peroxisomes were also required for resolution of bacterial infection through canonical innate immune signaling. Reduced peroxisome function impaired the turnover of the oxidative burst necessary to fight infection. This impaired response to bacterial challenge affected cell and organism survival and revealed a previously unknown requirement for peroxisomes in phagocytosis and innate immunity.
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•Peroxisomes are necessary for phagocytosis by Drosophila and mouse macrophages•Peroxisomes are required for resolution of microbial infection•Peroxisomes modulate innate immune pathways necessary to fight infection•Lack of functional peroxisomes affects organism survival in response to infection
Peroxisomes are organelles involved in lipid metabolism and reactive oxygen species turnover. Di Cara et al. now show that peroxisomes are required to resolve microbial infection by innate immunity. Peroxisomes assist in the progression of phagocytosis and activate innate immune signaling to promote survival in the face of microbial challenge.
Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and ...functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care.
•There is a pressing need for formalized clinical guidelines for PBD-ZSD.•We provide an overview of current clinical approaches for the diagnosis of PBD-ZSD.•We provide treatment guidelines for the major affected organ systems in PBD-ZSD.•This is a starting point for effective clinical management of PBD-ZSD.
Cancer is irrevocably linked to aberrant metabolic processes. While once considered a vestigial organelle, we now know that peroxisomes play a central role in the metabolism of reactive oxygen ...species, bile acids, ether phospholipids (e.g. plasmalogens), very-long chain, and branched-chain fatty acids. Immune system evasion is a hallmark of cancer, and peroxisomes have an emerging role in the regulation of cellular immune responses. Investigations of individual peroxisome proteins and metabolites support their pro-tumorigenic functions. However, a significant knowledge gap remains regarding how individual functions of proteins and metabolites of the peroxisome orchestrate its potential role as a pro-tumorigenic organelle. This review highlights new advances in our understanding of biogenesis, enzymatic functions, and autophagic degradation of peroxisomes (pexophagy), and provides evidence linking these activities to tumorigenesis. Finally, we propose avenues that may be exploited to target peroxisome-related processes as a mode of combatting cancer.
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Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of ...metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder. Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medications, or combination of therapies that help to achieve that goal in an individual, without other negative consequences, should be considered appropriate therapy. Significant evidence gaps remain in our understanding of the optimum therapies for phenylalanine hydroxylase deficiency, nonphenylalanine effects of these therapies, and long-term sequelae of even well-treated disease in children and adults.
Ethanolamine plasmalogens constitute a group of ether glycerophospholipids that, due to their unique biophysical and biochemical properties, are essential components of mammalian cellular membranes. ...Their importance is emphasized by the consequences of defects in plasmalogen biosynthesis, which in humans cause the fatal disease rhizomelic chondrodysplasia punctata (RCDP). In the present lipidomic study, we used fibroblasts derived from RCDP patients, as well as brain tissue from plasmalogen-deficient mice, to examine the compensatory mechanisms of lipid homeostasis in response to plasmalogen deficiency. Our results show that phosphatidylethanolamine (PE), a diacyl glycerophospholipid, which like ethanolamine plasmalogens carries the head group ethanolamine, is the main player in the adaptation to plasmalogen insufficiency. PE levels were tightly adjusted to the amount of ethanolamine plasmalogens so that their combined levels were kept constant. Similarly, the total amount of polyunsaturated fatty acids (PUFAs) in ethanolamine phospholipids was maintained upon plasmalogen deficiency. However, we found an increased incorporation of arachidonic acid at the expense of docosahexaenoic acid in the PE fraction of plasmalogen-deficient tissues. These data show that under conditions of reduced plasmalogen levels, the amount of total ethanolamine phospholipids is precisely maintained by a rise in PE. At the same time, a shift in the ratio between ω-6 and ω-3 PUFAs occurs, which might have unfavorable, long-term biological consequences. Therefore, our findings are not only of interest for RCDP but may have more widespread implications also for other disease conditions, as for example Alzheimer's disease, that have been associated with a decline in plasmalogens.
•PE accurately compensates for the lack of plasmalogens in vitro and in vivo.•PE levels decrease to adapt to excess of ethanolamine plasmalogens (PlsEtn).•Plasmalogen deficiency favors incorporation of arachidonic acid into PE.•Docosahexaenoic acid in ethanolamine phospholipids decreases upon PlsEtn depletion.
Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles, present in virtually every ...eukaryotic cell and mediating key processes in immunometabolism. To date, the full spectrum of PBDs remains to be identified, and the impact PBDs have on immune function is unexplored. This study presents a characterization of the hepatic immune compartment of a neonatal PBD mouse model at single-cell resolution to establish the importance and function of peroxisomes in developmental hematopoiesis. We report that hematopoietic defects are a feature in a severe PBD murine model. Finally, we identify a role for peroxisomes in the regulation of the major histocompatibility class II expression and antigen presentation to CD4+ T cells in dendritic cells. This study adds to our understanding of the mechanisms of PBDs and expands our knowledge of the role of peroxisomes in immunometabolism.
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•Peroxisomes are required for developmental hematopoiesis in mouse•PBD-ZSS murine model has defects in B cell, granulocyte, and cDC development•Peroxisomal DAG in DC regulates PKC-δ-mediated expression of MHC class II•Hematopoietic defects may be a feature of PBD-ZSS spectrum
Parsons et al. report that peroxisomes are required for hepatic hematopoiesis. They found hematopoietic defects in granulocytes, dendritic cells, and B cells of Pex2−/− Zellweger syndrome mice. Finally, they demonstrated that peroxisomes control the diacylglycerol-mediated activation of PKC-δ to drive MHC class II expression for effective antigen presentation to CD4+ T lymphocytes.
The biological impact of ether glycerophospholipids (GP) in peroxisomal disorders and other diseases makes them significant targets as biomarkers for diagnostic assays or deciphering pathology of the ...disorders. Ether lipids include both plasmanyl and plasmenyl lipids, which each contain an ether or a vinyl ether bond at the sn-1 linkage position, respectively. This linkage, in contrast to traditional diacyl GPs, precludes their detailed characterization by mass spectrometry via traditional collisional-based MS/MS techniques. Additionally, the isomeric nature of plasmanyl and plasmenyl pairs of ether lipids introduces a further level of complexity that impedes analysis of these species. Here, we utilize 213 nm ultraviolet photodissociation mass spectrometry (UVPD-MS) for detailed characterization of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) plasmenyl and plasmanyl lipids in mouse brain tissue. 213 nm UVPD-MS enables the successful differentiation of these four ether lipid subtypes for the first time. We couple this UVPD-MS methodology to reversed-phase liquid chromatography (RPLC) for characterization and relative quantitation of ether lipids from normal and diseased (Pex7 deficiency modeling the peroxisome biogenesis disorder, RCDP) mouse brain tissue, highlighting the ability to pinpoint specific structural features of ether lipids that are important for monitoring aberrant lipid metabolism in peroxisomal disorders.
•Plasmalogens are glycerophospholipids crucial to cellular membrane structure and function.•Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders, particularly ...rhizomelic chondrodysplasia punctata (RCDP)•We developed a liquid-chromatography/tandem mass-spectrometry method to quantify plasmalogens in red blood cells (RBCs)•We have demonstrated clinical utility of our method in diagnosing peroxisome biogenesis disorders using RBCs from controls, known patients and RCDP1 mouse models.
Plasmalogens are glycerophospholipids characterized by a vinyl-ether bond with a fatty alcohol at the sn-1 position, a polyunsaturated fatty acid at the sn-2 position, and a polar head at the sn-3 position, commonly phosphoethanolamine. Plasmalogens play crucial roles in several cellular processes. Reduced levels have been associated with Alzheimer’s and Parkinson’s disease progression. Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes. Particularly, severe plasmalogen deficiency is the biochemical hallmark of rhizomelic chondrodysplasia punctata (RCDP). Traditionally, plasmalogens are evaluated in red blood cells (RBCs) by gas-chromatography/mass-spectrometry (GC–MS), which cannot distinguish individual species. We developed a liquid-chromatography/tandem mass-spectrometry (LC-MS/MS) method to quantify eighteen phosphoethanolamine plasmalogens in RBCs to diagnose PBD patients, especially RCDP. Validation results showed a specific, robust, and precise method with broad analytical range. Age-specific reference intervals were established; control medians were used to assess plasmalogen deficiency in patients’ RBCs. Clinical utility was also confirmed in Pex7 deficient mouse models recapitulating severe and milder RCDP clinical phenotypes. To our knowledge, this is the first attempt to replace the GC–MS method in the clinical laboratory. In addition to diagnosing PBDs, structure-specific plasmalogen quantitation could help understand disease pathogenesis and monitor therapy.
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