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Respiratory Research Dec 2023It is now understood that ferroptosis plays a significant role in the progression of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke extract...
BACKGROUND
It is now understood that ferroptosis plays a significant role in the progression of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke extract (CSE). However, the mechanisms underlying this relationship remain largely unclear.
METHODS
In this study, we established a COPD mouse model through exposure to cigarette smoke particulates, followed by H&E staining, analysis of bronchoalveolar lavage fluid, and immunohistochemistry assay. A549 cells were exposed to increasing concentrations of CSE, with the addition of the ferroptosis activator erastin or the inhibitor Fer-1. Cell viability, LDH (lactate dehydrogenase) release, inflammatory cytokines, total ROS (reactive oxygen species), and lipid ROS were measured using the corresponding assay kits. The acetylation level of GNPAT was determined through immunoprecipitation. We assessed the expression levels of molecules involved in plasmalogen biosynthesis (FAR1, AGPS, and GNPAT), GPX4, and SIRT4 using quantitative real-time PCR, western blot analysis, and immunofluorescence staining.
RESULTS
CSE-induced lung tissue damage was initially observed, accompanied by oxidative stress, ferroptosis, and increased plasmalogen biosynthesis molecules (FAR1, AGPS, and GNPAT). CSE also induced ferroptosis in A549 cells, resulting in reduced cell viability, GSH, and GPX4 levels, along with increased LDH, ROS, MDA (malondialdehyde) levels, oxidized lipids, and elevated FAR1, AGPS, and GNPAT expression. Knockdown of GNPAT mitigated CSE-induced ferroptosis. Furthermore, we found that CSE regulated the acetylation and protein levels of GNPAT by modulating SIRT4 expression. Importantly, the overexpression of GNPAT countered the inhibitory effects of SIRT4 on ferroptosis.
CONCLUSIONS
Our study revealed GNPAT could be deacetylated by SIRT4, providing novel insights into the mechanisms underlying the relationship between CSE-induced ferroptosis and COPD.
Topics: Mice; Animals; Ferroptosis; Reactive Oxygen Species; Plasmalogens; Pulmonary Disease, Chronic Obstructive; Lung; Nicotiana
PubMed: 38041059
DOI: 10.1186/s12931-023-02613-0 -
Journal of Inherited Metabolic Disease Jan 2022Barth syndrome (BTHS) is a rare inherited metabolic disease resulting from mutations in the gene of the enzyme tafazzin, which catalyzes the acyl chain remodeling of the... (Review)
Review
Barth syndrome (BTHS) is a rare inherited metabolic disease resulting from mutations in the gene of the enzyme tafazzin, which catalyzes the acyl chain remodeling of the mitochondrial-specific lipid cardiolipin (CL). Tissue samples of individuals with BTHS present abnormalities in the level and the molecular species of CL. In addition, in tissues of a tafazzin knockdown mouse as well as in cells derived from BTHS patients it has been shown that plasmalogens, a subclass of glycerophospholipids, also have abnormal levels. Likewise, administration of a plasmalogen precursor to cells derived from BTHS patients led to an increase in plasmalogen and to some extent CL levels. These results indicate an interplay between CL and plasmalogens in BTHS. This interdependence is supported by the concomitant loss in these lipids in different pathological conditions. However, currently the molecular mechanism linking CL and plasmalogens is not fully understood. Here, a review of the evidence showing the linkage between the levels of CL and plasmalogens is presented. In addition, putative mechanisms that might play a role in this interplay are proposed. Finally, the opportunity of therapeutic approaches based on the regulation of plasmalogens as new therapies for the treatment of BTHS is discussed.
Topics: Acyltransferases; Animals; Barth Syndrome; Cardiolipins; Humans; Mice; Mitochondria; Mutation; Plasmalogens
PubMed: 34655242
DOI: 10.1002/jimd.12449 -
Biochimica Et Biophysica Acta.... Jul 2020Long-chain fatty aldehydes are present in low concentrations in mammalian cells and serve as intermediates in the interconversion between fatty acids and fatty alcohols.... (Review)
Review
Long-chain fatty aldehydes are present in low concentrations in mammalian cells and serve as intermediates in the interconversion between fatty acids and fatty alcohols. The long-chain fatty aldehydes are generated by enzymatic hydrolysis of 1-alkyl-, and 1-alkenyl-glycerophospholipids by alkylglycerol monooxygenase, plasmalogenase or lysoplasmalogenase while hydrolysis of sphingosine-1-phosphate (S1P) by S1P lyase generates trans ∆2-hexadecenal (∆2-HDE). Additionally, 2-chloro-, and 2-bromo- fatty aldehydes are produced from plasmalogens or lysoplasmalogens by hypochlorous, and hypobromous acid generated by activated neutrophils and eosinophils, respectively while 2-iodofatty aldehydes are produced by excess iodine in thyroid glands. The 2-halofatty aldehydes and ∆2-HDE activated JNK signaling, BAX, cytoskeletal reorganization and apoptosis in mammalian cells. Further, 2-chloro- and 2-bromo-fatty aldehydes formed GSH and protein adducts while ∆2-HDE formed adducts with GSH, deoxyguanosine in DNA and proteins such as HDAC1 in vitro. ∆2-HDE also modulated HDAC activity and stimulated H3 and H4 histone acetylation in vitro with lung epithelial cell nuclear preparations. The α-halo fatty aldehydes elicited endothelial dysfunction, cellular toxicity and tissue damage. Taken together, these investigations suggest a new role for long-chain fatty aldehydes as signaling lipids, ability to form adducts with GSH, proteins such as HDACs and regulate cellular functions.
Topics: Aldehyde-Lyases; Aldehydes; Animals; Histone Deacetylases; Humans; Plasmalogens; Signal Transduction
PubMed: 32171908
DOI: 10.1016/j.bbalip.2020.158681 -
Frontiers in Molecular Biosciences 2022The presence of plasmalogens in bacteria has been known for 60 years. The recent discovery of two genes encoding reductases that convert diacyl lipids to 1-alk-1'-enyl... (Review)
Review
The presence of plasmalogens in bacteria has been known for 60 years. The recent discovery of two genes encoding reductases that convert diacyl lipids to 1-alk-1'-enyl 2-acyl lipids has confirmed the derivation of plasmalogens from the corresponding diacyl lipids in bacteria. These genes are widely distributed in anaerobic and in some facultatively anaerobic bacteria. Plasmalogens evolved very early in the history of life on earth. Their persistence during eons of evolution suggests that they play a fundamental role in living organism. The phase behavior of plasmalogens and their conformation in membranes is discussed.
PubMed: 36452453
DOI: 10.3389/fmolb.2022.962757 -
Frontiers in Cell and Developmental... 2022Due to their unique chemical structure, plasmalogens do not only exhibit distinct biophysical and biochemical features, but require specialized pathways of biosynthesis... (Review)
Review
Due to their unique chemical structure, plasmalogens do not only exhibit distinct biophysical and biochemical features, but require specialized pathways of biosynthesis and metabolization. Recently, major advances have been made in our understanding of these processes, for example by the attribution of the gene encoding the enzyme, which catalyzes the final desaturation step in plasmalogen biosynthesis, or by the identification of cytochrome C as plasmalogenase, which allows for the degradation of plasmalogens. Also, models have been presented that plausibly explain the maintenance of adequate cellular levels of plasmalogens. However, despite the progress, many aspects around the questions of how plasmalogen metabolism is regulated and how plasmalogens are distributed among organs and tissues in more complex organisms like mammals, remain unresolved. Here, we summarize and interpret current evidence on the regulation of the enzymes involved in plasmalogen biosynthesis and degradation as well as the turnover of plasmalogens. Finally, we focus on plasmalogen traffic across the mammalian body - a topic of major importance, when considering plasmalogen replacement therapies in human disorders, where deficiencies in these lipids have been reported. These involve not only inborn errors in plasmalogen metabolism, but also more common diseases including Alzheimer's disease and neurodevelopmental disorders.
PubMed: 36120579
DOI: 10.3389/fcell.2022.946393 -
Lipids in Health and Disease Apr 2019Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer's disease (AD). Decreased levels... (Review)
Review
Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer's disease (AD). Decreased levels of PlsEtns have been commonly found in AD patients, and were correlated with cognition deficit and severity of disease. Limited studies showed positive therapeutic outcomes with plasmalogens interventions in AD subjects and in rodents. The potential mechanisms underlying the beneficial effects of PlsEtns on AD may be related to the reduction of γ-secretase activity, an enzyme that catalyzes the synthesis of β-amyloid (Aβ), a hallmark of AD. Emerging in vitro evidence also showed that PlsEtns prevented neuronal cell death by enhancing phosphorylation of AKT and ERK signaling through the activation of orphan G-protein coupled receptor (GPCR) proteins. In addition, PlsEtns have been found to suppress the death of primary mouse hippocampal neuronal cells through the inhibition of caspase-9 and caspase-3 cleavages. Further in-depth investigations are required to determine the signature molecular species of PlsEtns associated with AD, hence their potential role as biomarkers. Clinical intervention with plasmalogens is still in its infancy but may have the potential to be explored for a novel therapeutic approach to correct AD pathology and neural function.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Biomarkers; Cell Death; Cognitive Dysfunction; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Neurons; Plasmalogens; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; Severity of Illness Index; Signal Transduction
PubMed: 30992016
DOI: 10.1186/s12944-019-1044-1 -
Frontiers in Cell and Developmental... 2022Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and... (Review)
Review
Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and organelles but also fuel substrates for energy production. However, our current knowledge of lipid processing in the retina are very limited. Peroxisomes play a critical role in lipid homeostasis and genetic disorders with peroxisomal dysfunction have different types of ocular complications. In this review, we focus on the role of peroxisomes in lipid metabolism, including degradation and detoxification of very-long-chain fatty acids, branched-chain fatty acids, dicarboxylic acids, reactive oxygen/nitrogen species, glyoxylate, and amino acids, as well as biosynthesis of docosahexaenoic acid, plasmalogen and bile acids. We also discuss the potential contributions of peroxisomal pathways to eye health and summarize the reported cases of ocular symptoms in patients with peroxisomal disorders, corresponding to each disrupted peroxisomal pathway. We also review the cross-talk between peroxisomes and other organelles such as lysosomes, endoplasmic reticulum and mitochondria.
PubMed: 36187472
DOI: 10.3389/fcell.2022.982564 -
Brain Research Bulletin Sep 2023After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term... (Review)
Review
Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome.
After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties ("brain fog"), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions. Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.
Topics: Humans; Fatigue Syndrome, Chronic; Plasmalogens; Post-Acute COVID-19 Syndrome; COVID-19; Inflammation
PubMed: 37423295
DOI: 10.1016/j.brainresbull.2023.110702 -
BioFactors (Oxford, England) Nov 2022Fatty acids and phospholipid molecules are essential for determining the structure and function of cell membranes, and they hence participate in many biological... (Review)
Review
Fatty acids and phospholipid molecules are essential for determining the structure and function of cell membranes, and they hence participate in many biological processes. Platelet activating factor (PAF) and its precursor plasmalogen, which represent two subclasses of ether phospholipids, have attracted increasing research attention recently due to their association with multiple chronic inflammatory, neurodegenerative, and metabolic disorders. These pathophysiological conditions commonly involve inflammatory processes linked to an excess presence of PAF and/or decreased levels of plasmalogens. However, the molecular mechanisms underlying the roles of plasmalogens in inflammation have remained largely elusive. While anti-inflammatory responses most likely involve the plasmalogen signal pathway; pro-inflammatory responses recruit arachidonic acid, a precursor of pro-inflammatory lipid mediators which is released from membrane phospholipids, notably derived from the hydrolysis of plasmalogens. Plasmalogens per se are vital membrane phospholipids in humans. Changes in their homeostatic levels may alter cell membrane properties, thus affecting key signaling pathways that mediate inflammatory cascades and immune responses. The plasmalogen analogs of PAF are also potentially important, considering that anti-PAF activity has strong anti-inflammatory effects. Plasmalogen replacement therapy was further identified as a promising anti-inflammatory strategy allowing for the relief of pathological hallmarks in patients affected by chronic diseases with an inflammatory component. The aim of this Short Review is to highlight the emerging roles and implications of plasmalogens in chronic inflammatory disorders, along with the promising outcomes of plasmalogen replacement therapy for the treatment of various PAF-related chronic inflammatory pathologies.
Topics: Humans; Plasmalogens; Platelet Activating Factor; Phospholipid Ethers; Cell Membrane; Chronic Disease
PubMed: 36370412
DOI: 10.1002/biof.1916 -
Brain Research Bulletin Oct 2022Ether phospholipid compositions are altered in the plasma or brain of patients with brain disorders, such as Alzheimer and Parkinson's disease, including those with... (Review)
Review
Ether phospholipid compositions are altered in the plasma or brain of patients with brain disorders, such as Alzheimer and Parkinson's disease, including those with psychiatric disorders like schizophrenia and bipolar disorders. Notably, plasmenyl ethanolamine has a unique chemical structure, i.e., a vinyl-ether bond at the sn-1 position, which mainly links with polyunsaturated fatty acids (PUFAs) at the sn-2 position. Those characteristic moieties give plasmalogen molecules unique biophysical and chemical properties that modulate membrane trafficking, lipid rafts, intramolecular PUFA moieties, and oxidative states. Previous reports suggested that a deficiency in plasmenyl ethanolamine leads to disturbances of the myelin structure, synaptic neurotransmission and intracellular signaling, apoptosis of neurons, and neuroinflammation, accompanied by cognitive disturbances and aberrant behaviors like hyperactivity in mice. Therefore, this review summarizes the relationship between the biological functions of plasmalogen. We also proposed biophysical properties that alter brain phospholipid compositions related to aberrant behaviors and cognitive dysfunction. Finally, a brief review of possible remedial plasmalogen replacement therapies for neurological, psychiatric, and developmental disorders attributable to disturbed plasmalogen compositions in the organs and cells was conducted.
Topics: Animals; Brain; Cognition; Ethanolamines; Humans; Mice; Oxidation-Reduction; Plasmalogens
PubMed: 35970332
DOI: 10.1016/j.brainresbull.2022.08.008