RESUMEN
The malate aspartate shuttle (MAS) plays a pivotal role in transporting cytosolic reducing equivalents - electrons - into the mitochondria for energy conversion at the electron transport chain (ETC) and in the process of oxidative phosphorylation. The MAS consists of two pairs of cytosolic and mitochondrial isoenzymes (malate dehydrogenases 1 and 2; and glutamate oxaloacetate transaminases 1 and 2) and two transporters (malate-2-oxoglutarate carrier and aspartate glutamate carrier (AGC), the latter of which has two tissue-dependent isoforms AGC1 and AGC2). While the inner mitochondrial membrane is impermeable to NADH, the MAS forms one of the main routes for mitochondrial electron uptake by promoting uptake of malate. Inherited bi-allelic pathogenic variants in five of the seven components of the MAS have been described hitherto and cause a wide spectrum of symptoms including early-onset epileptic encephalopathy. This review provides an overview of reported patients suffering from MAS deficiencies. In addition, we give an overview of diagnostic procedures and research performed on patient-derived cellular models and tissues. Current cellular models are briefly discussed and novel ways to achieve a better understanding of MAS deficiencies are highlighted.
Asunto(s)
Ácido Aspártico , Malato Deshidrogenasa , Malatos , Mitocondrias , Humanos , Malatos/metabolismo , Malato Deshidrogenasa/metabolismo , Malato Deshidrogenasa/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Mitocondrias/patología , Ácido Aspártico/metabolismo , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/patología , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/diagnóstico , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/deficiencia , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Fosforilación Oxidativa , AntiportadoresRESUMEN
Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.
Asunto(s)
Adiponectina , Modelos Animales de Enfermedad , Hepatocitos , Enfermedad del Hígado Graso no Alcohólico , Animales , Adiponectina/metabolismo , Adiponectina/farmacología , Adiponectina/deficiencia , Ratones , Humanos , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Masculino , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/patología , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/prevención & control , Enfermedades Metabólicas/etiología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado Graso/prevención & control , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/patologíaRESUMEN
Inborn errors of metabolism (IEM) represent a heterogeneous group of more than 1800 rare disorders, many of which are causing significant childhood morbidity and mortality. More than 100 IEM are linked to dyslipidaemia, but yet our knowledge in connecting genetic information with lipidomic data is limited. Stable isotope tracing studies of the lipid metabolism (STL) provide insights on the dynamic of cellular lipid processes and could thereby facilitate the delineation of underlying metabolic (patho)mechanisms. This mini-review focuses on principles as well as technical limitations of STL and describes potential clinical applications by discussing recently published STL focusing on IEM.
Asunto(s)
Metabolismo de los Lípidos , Lipidómica , Humanos , Lipidómica/métodos , Metabolismo de los Lípidos/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/genética , Animales , Lípidos/genética , Marcaje Isotópico/métodosRESUMEN
The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup of disorders that present with neurodevelopmental disability. The chromatin machinery regulates gene expression by a range of mechanisms, including by post-translational modification of histones, responding to histone marks, and remodelling nucleosomes. Some of the MDCMs that impact on histone modification may have potential therapeutic interventions. Two potential treatment strategies are to enhance the intracellular pool of metabolites that can act as substrates for histone modifiers and the use of medications that may inhibit or promote the modification of histone residues to influence gene expression. In this article we discuss the influence and potential treatments of histone modifications involving histone acetylation and histone methylation. Genomic technologies are facilitating earlier diagnosis of many Mendelian disorders, providing potential opportunities for early treatment from infancy. This has parallels with how inborn errors of metabolism have been afforded early treatment with newborn screening. Before this promise can be fulfilled, we require greater understanding of the biochemical fingerprint of these conditions, which may provide opportunities to supplement metabolites that can act as substrates for chromatin modifying enzymes. Importantly, understanding the metabolomic profile of affected individuals may also provide disorder-specific biomarkers that will be critical for demonstrating efficacy of treatment, as treatment response may not be able to be accurately assessed by clinical measures.
Asunto(s)
Cromatina , Redes y Vías Metabólicas , Humanos , Cromatina/genética , Cromatina/metabolismo , Redes y Vías Metabólicas/genética , Histonas/metabolismo , Histonas/genética , Procesamiento Proteico-Postraduccional , Acetilación , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Ensamble y Desensamble de Cromatina/genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/metabolismo , Recién Nacido , MetilaciónRESUMEN
Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive inherited disorder related to lipid metabolism affecting skeletal muscle. The first cases of CPT II deficiency causing myopathy were reported in 1973. In 1983, Werneck et al published the first two Brazilian patients with myopathy due to CPT II deficiency, where the biochemical analysis confirmed deficient CPT activity in the muscle of both cases. Over the past 40 years since the pioneering publication, clinical phenotypes and genetic loci in the CPT2 gene have been described, and pathogenic mechanisms have been better elucidated. Genetic analysis of one of the original cases disclosed compound heterozygous pathogenic variants (p.Ser113Leu/p.Pro50His) in the CPT2 gene. Our report highlights the historical aspects of the first Brazilian publication of the myopathic form of CPT II deficiency and updates the genetic background of this pioneering publication.
Deficiência de carnitina palmitoiltransferase II (CPT II) é uma desordem de herança autossômica recessiva relacionada com o metabolismo do lipídio afetando músculo esquelético. Os primeiros dois casos de deficiência de CPT II causando miopatia foram relatados em 1973. Em 1983, Werneck et al. publicaram os primeiros pacientes brasileiros com miopatia por deficiência de CPT II, nos quais a análise bioquímica confirmou a atividade deficiente da CPT nos músculos em ambos os casos. Após 40 anos desde a publicação pioneira, fenótipos clínicos e loci genético no gene CPT2 foram descritos, bem com os mecanismos patológicos foram melhor elucidados. A análise genética de um dos casos da publicação original apresentou variantes patogênicas em heterozigose composta (p.Ser113Leu/p.Pro50His) no gene CPT2. O nosso relato destaca os aspectos históricos da primeira publicação brasileira da forma miopática da deficiência de CPT II e atualiza as bases genéticas dessa publicação pioneira.
Asunto(s)
Carnitina O-Palmitoiltransferasa/deficiencia , Errores Innatos del Metabolismo , Enfermedades Musculares , Humanos , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Brasil , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , MutaciónRESUMEN
Inborn errors of metabolism (IEMs) encompass a diverse group of disorders that can be difficult to classify due to heterogenous clinical, molecular, and biochemical manifestations. Untargeted metabolomics platforms have become a popular approach to analyze IEM patient samples because of their ability to detect many metabolites at once, accelerating discovery of novel biomarkers, and metabolic mechanisms of disease. However, there are concerns about the reproducibility of untargeted metabolomics research due to the absence of uniform reporting practices, data analyses, and experimental design guidelines. Therefore, we critically evaluated published untargeted metabolomic platforms used to characterize IEMs to summarize the strengths and areas for improvement of this technology as it progresses towards the clinical laboratory. A total of 96 distinct IEMs were collectively evaluated by the included studies. However, most of these IEMs were evaluated by a single untargeted metabolomic method, in a single study, with a limited cohort size (55/96, 57%). The goals of the included studies generally fell into two, often overlapping, categories: detecting known biomarkers from many biochemically distinct IEMs using a single platform, and detecting novel metabolites or metabolic pathways. There was notable diversity in the design of the untargeted metabolomic platforms. Importantly, the majority of studies reported adherence to quality metrics, including the use of quality control samples and internal standards in their experiments, as well as confirmation of at least some of their feature annotations with commercial reference standards. Future applications of untargeted metabolomics platforms to the study of IEMs should move beyond single-subject analyses, and evaluate reproducibility using a prospective, or validation cohort.
Asunto(s)
Errores Innatos del Metabolismo , Humanos , Reproducibilidad de los Resultados , Estudios Prospectivos , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Metabolómica/métodos , Biomarcadores/metabolismoRESUMEN
Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies.
Asunto(s)
Prueba de Esfuerzo , Errores Innatos del Metabolismo , Adulto , Niño , Humanos , Músculo Esquelético/metabolismo , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Errores Innatos del Metabolismo/metabolismo , Metabolismo Energético/fisiología , PrescripcionesRESUMEN
Metabolic myopathies are a set of rare inborn errors of metabolism leading to disruption in energy production. Relevant to skeletal muscle, glycogen storage disease and fatty acid oxidation defects can lead to exercise intolerance, rhabdomyolysis, and weakness in children and adults, distinct from the severe forms that involve multiple-organ systems. These nonspecific, dynamic symptoms along with conditions that mimic metabolic myopathies can make diagnosis challenging. Clinicians can shorten the time to diagnosis by recognizing the typical clinical phenotypes and performing next generation sequencing. With improved access and affordability of molecular testing, clinicians need to be well-versed in resolving variants of uncertain significance relevant to metabolic myopathies. Once identified, patients can improve quality of life, safely engage in exercise, and reduce episodes of rhabdomyolysis by modifying diet and lifestyle habits.
Asunto(s)
Errores Innatos del Metabolismo , Miopatías Mitocondriales , Enfermedades Musculares , Rabdomiólisis , Humanos , Calidad de Vida , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/terapia , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Músculo Esquelético/metabolismo , Miopatías Mitocondriales/diagnósticoRESUMEN
Determination of urine organic acids (UOAs) is essential to understand the disease progress of inborn errors of metabolism (IEM) and often relies on GC-MS analysis. However, the efficiency of analytical reports is sometimes restricted by data processing due to labor-intensive work if no proper tool is employed. Herein, we present a simple and rapid workflow with an R-based script for automated data processing (AutoDP) of GC-MS raw files to quantitatively analyze essential UOAs. AutoDP features automatic quality checks, compound identification and confirmation with specific fragment ions, retention time correction from analytical batches, and visualization of abnormal UOAs with age-matched references on chromatograms. Compared with manual processing, AutoDP greatly reduces analytical time and increases the number of identifications. Speeding up data processing is expected to shorten the waiting time for clinical diagnosis, which could greatly benefit clinicians and patients with IEM. In addition, with quantitative results obtained from AutoDP, it would be more feasible to perform retrospective analysis of specific UOAs in IEM and could provide new perspectives for studying IEM.
Asunto(s)
Errores Innatos del Metabolismo , Humanos , Cromatografía de Gases y Espectrometría de Masas/métodos , Estudios Retrospectivos , Flujo de Trabajo , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismoRESUMEN
Inborn errors of metabolism (IEMs) are characterized by deficits in metabolic enzymes as a result of an inherited disease, leading to the accumulation or decreased excretion of proteins, carbohydrates and lipids. Although IEMs are often diagnosed during childhood, adolescent and adult onset variants may be accompanied by less somatic and more psychiatric manifestations, which often hampers recognition by psychiatrists of the distinction between a primary and secondary psychiatric disorder. To help clinicians in the diagnostic process, we aimed to provide an overview of psychiatric manifestations in IEMs. Our literature search yielded 4380 records in total, of which 88 studies were included in the qualitative synthesis. Reported psychiatric disorders in adolescent and adult IEMs included depression, anxiety disorder, psychosis, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder and obsessive-compulsive disorder as assessed by semi-structured diagnostic interviews and validated questionnaires. A diagnostic screener and multidisciplinary IEM clinics are proposed to help clinicians during the diagnostic process, to prevent diagnostic delay and to raise awareness of the psychiatric manifestations among IEMs.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Bipolar , Errores Innatos del Metabolismo , Trastornos Psicóticos , Adulto , Adolescente , Humanos , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Trastorno del Espectro Autista/complicaciones , Diagnóstico Tardío , Trastornos Psicóticos/complicaciones , Trastorno Bipolar/complicacionesRESUMEN
There are about 1500 genetic metabolic diseases. A small number of treatable diseases are diagnosed by newborn screening programs, which are continually being developed. However, most diseases can only be diagnosed based on clinical symptoms or metabolic findings. The main biological fluids used are urine, plasma and, in special situations, cerebrospinal fluid. In contrast to commonly used methods such as gas chromatography and high performance liquid chromatography mass spectrometry, ex vivo proton spectroscopy (1 H-NMR) is not yet used in routine clinical practice, although it has been recommended for more than 30 years. Automatic analysis and improved NMR technology have also expanded the applications used for the diagnosis of inborn errors of metabolism. We provide a mini-overview of typical applications, especially in urine but also in plasma, used to diagnose common but also rare genetic metabolic diseases with 1 H-NMR. The use of computer-assisted diagnostic suggestions can facilitate interpretation of the profiles. In a proof of principle, to date, 182 reports of 59 different diseases and 500 reports of healthy children are stored. The percentage of correct automatic diagnoses was 74%. Using the same 1 H-NMR profile-targeted analysis, it is possible to apply an untargeted approach that distinguishes profile differences from healthy individuals. Thus, additional conditions such as lysosomal storage diseases or drug interferences are detectable. Furthermore, because 1 H-NMR is highly reproducible and can detect a variety of different substance categories, the metabolomic approach is suitable for monitoring patient treatment and revealing additional factors such as nutrition and microbiome metabolism. Besides the progress in analytical techniques, a multiomics approach is most effective to combine metabolomics with, for example, whole exome sequencing, to also diagnose patients with nondetectable metabolic abnormalities in biological fluids. In this mini review we also provide our own data to demonstrate the role of NMR in a multiomics platform in the field of inborn errors of metabolism.
Asunto(s)
Errores Innatos del Metabolismo , Niño , Recién Nacido , Humanos , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Protones , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , ComputadoresRESUMEN
A patient suspected of an inborn error of metabolism will commonly have urine organic acid analysis performed as part of their workup. The traditional urine organic acid method involves extraction of the acidic fraction from urine samples using an organic solvent, derivatization of extracted compounds, and identification using gas chromatography-mass spectrometry (GC/MS). Unfortunately, the extraction step results in the loss of many neutral and positively charged compounds which may be of interest to metabolic physicians and biochemical geneticists. By replacing the traditional extraction step with an enzymatic treatment of the sample with urease, an abundance of organic molecules is available for separation and quantification by GC/MS. The urease method is a useful adjunct to newborn screening follow-up, and it has the additional benefit of being able to identify many classes of biochemical compounds, such as amino acids, acylglycines, neurotransmitters, and carbohydrates. This method describes the urease treatment, derivatization, and the organic acids and other biochemical metabolites that can be identified.
Asunto(s)
Errores Innatos del Metabolismo , Ureasa , Ácidos , Aminas , Aminoácidos , Carbohidratos , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Recién Nacido , Errores Innatos del Metabolismo/metabolismo , SolventesRESUMEN
Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1-/- ) were embryonically lethal, whereas homozygous KI (Gfm1R671C/R671C ) mice were viable and showed normal growth. R671C mutation in Gfm1 caused drastic reductions in the mitochondrial EFG1 protein content in different organs. Six- to eight-week-old Gfm1R671C/R671C mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1R671C/- showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1R671C/R671C mice. At 8 weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1R671C/- mice showed combined oxidative phosphorylation deficiency (reduced complex I and IV enzyme activities in liver and brain), and blue native polyacrylamide gel electrophoresis analysis revealed lower amounts of both affected complexes. We conclude that the compound heterozygous Gfm1R671C/- mouse presents a clear dysfunctional molecular phenotype, showing impaired mitochondrial translation and combined respiratory chain dysfunction, making it a suitable animal model for the study of COXPD1.
Asunto(s)
Encefalopatía Hepática/metabolismo , Errores Innatos del Metabolismo/metabolismo , Mitocondrias Hepáticas/metabolismo , Proteínas Mitocondriales/metabolismo , Mutación Missense , Fosforilación Oxidativa , Factor G de Elongación Peptídica/metabolismo , Biosíntesis de Proteínas , Sustitución de Aminoácidos , Animales , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Encefalopatía Hepática/genética , Errores Innatos del Metabolismo/genética , Ratones , Ratones Noqueados , Mitocondrias Hepáticas/genética , Proteínas Mitocondriales/genética , Factor G de Elongación Peptídica/genéticaRESUMEN
In the diagnostic work-up of a newborn infant with a metabolic crisis, lethal multiorgan failure on day six of life, and increased excretion of 3-methylglutaconic acid, we found using whole genome sequencing a homozygous SERAC1 mutation indicating MEGDHEL syndrome (3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy, and Leigh-like syndrome). The SERAC1 protein is located at the contact site between mitochondria and the endoplasmic reticulum (ER) and is crucial for cholesterol trafficking. Our aim was to investigate the effect of the homozygous truncating mutation on mitochondrial structure and function. In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial network was severely fragmented, and the cristae morphology was altered. Filipin staining showed uneven localization of unesterified cholesterol. The calcium buffer function between cytoplasm and mitochondria was deficient. In liver mitochondria, complexes I, III, and IV were clearly decreased. In transfected COS-1 cells the mutant protein with the a 45-amino acid C-terminal truncation was distributed throughout the cell, whereas wild-type SERAC1 partially colocalized with the mitochondrial marker MT-CO1. The structural and functional mitochondrial abnormalities, caused by the loss of SERAC1, suggest that the crucial disease mechanism is disrupted interplay between the ER and mitochondria leading to decreased influx of calcium to mitochondria and secondary respiratory chain deficiency.
Asunto(s)
Hidrolasas de Éster Carboxílico/genética , Errores Innatos del Metabolismo/genética , Mitocondrias Hepáticas/genética , Enfermedades Mitocondriales/genética , Calcio/metabolismo , Colesterol/metabolismo , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Femenino , Glutaratos/metabolismo , Humanos , Recién Nacido , Masculino , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Secuenciación Completa del GenomaRESUMEN
Glucocorticoids (GCs) represent a well-known class of lipophilic steroid hormones biosynthesised, with a circadian rhythm, by the adrenal glands in humans and by the inter-renal tissue in teleost fish (e.g., zebrafish). GCs play a key role in the regulation of numerous physiological processes, including inflammation, glucose, lipid, protein metabolism and stress response. This is achieved through binding to their cognate receptor, GR, which functions as a ligand-activated transcription factor. Due to their potent anti-inflammatory and immune-suppressive action, synthetic GCs are broadly used for treating pathological disorders that are very often linked to hypoxia (e.g., rheumatoid arthritis, inflammatory, allergic, infectious, and autoimmune diseases, among others) as well as to prevent graft rejections and against immune system malignancies. However, due to the presence of adverse effects and GC resistance their therapeutic benefits are limited in patients chronically treated with steroids. For this reason, understanding how to fine-tune GR activity is crucial in the search for novel therapeutic strategies aimed at reducing GC-related side effects and effectively restoring homeostasis. Recent research has uncovered novel mechanisms that inhibit GR function, thereby causing glucocorticoid resistance, and has produced some surprising new findings. In this review we analyse these mechanisms and focus on the crosstalk between GR and HIF signalling. Indeed, its comprehension may provide new routes to develop novel therapeutic targets for effectively treating immune and inflammatory response and to simultaneously facilitate the development of innovative GCs with a better benefits-risk ratio.
Asunto(s)
Glucocorticoides/genética , Inflamación/genética , Errores Innatos del Metabolismo/genética , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/genética , Animales , Regulación de la Expresión Génica/genética , Glucocorticoides/metabolismo , Homeostasis/genética , Humanos , Inflamación/metabolismo , Inflamación/patología , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Unión Proteica/genética , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/genética , Pez Cebra/genéticaRESUMEN
Enzymatic methylation catalyzed by methyltransferases has a significant impact on many human biochemical reactions. As the second most ubiquitous cofactor in humans, S-adenosyl-l-methionine (SAM or AdoMet) serves as a methyl donor for SAM-dependent methyltransferases (MTases), which transfer a methyl group to a nucleophilic acceptor such as O, As, N, S, or C as the byproduct. SAM-dependent methyltransferases can be grouped into different types based on the substrates. Here we systematically reviewed eight types of methyltransferases associated with human diseases. Catechol O-methyltransferase (COMT), As(III) S-adenosylmethionine methyltransferase (AS3MT), indolethylamine N-methyltransferase (INMT), phenylethanolamine N-methyltransferase (PNMT), histamine N-methyltransferase (HNMT), nicotinamide N-methyltransferase (NNMT), thiopurine S-methyltransferase (TPMT) and DNA methyltansferase (DNMT) are classic SAM-dependent MTases. Correlations between genotypes and disease susceptibility can be partially explained by genetic polymorphisms. The physiological function, substrate specificity, genetic variants and disease susceptibility associated with these eight SAM-dependent methyltransferases are discussed in this review.
Asunto(s)
Errores Innatos del Metabolismo/genética , Metiltransferasas/genética , Polimorfismo de Nucleótido Simple , S-Adenosilmetionina/metabolismo , Animales , Humanos , Errores Innatos del Metabolismo/metabolismo , Metiltransferasas/química , Metiltransferasas/metabolismoRESUMEN
INTRODUCTION: Gain-of-function mutations in guanylyl cyclase C (GCC) result in persistent diarrhea with perinatal onset. We investigated a specific GCC inhibitor, SSP2518, for its potential to treat this disorder. METHODS: We investigated the effect of SSP2518 on GCC-mediated intracellular cyclic guanosine monophosphate (cGMP) levels and on GCC-mediated chloride secretion in intestinal organoids from 3 patients with distinct activating GCC mutations and from controls, with and without stimulation of GCC with heat-stable enterotoxin. RESULTS: Patient-derived organoids had significantly higher basal cGMP levels than control organoids, which were lowered by SSP2518 to levels found in control organoids. In addition, SSP2518 significantly reduced cGMP levels and chloride secretion in patient-derived and control organoids (P < 0.05 for all comparisons) after heat-stable enterotoxin stimulation. DISCUSSION: We reported in this study that the GCC inhibitor SSP2518 normalizes cGMP levels in intestinal organoids derived from patients with GCC gain-of-function mutations and markedly reduces cystic fibrosis transmembrane conductance regulator-dependent chloride secretion, the driver of persistent diarrhea.
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Anomalías Múltiples/tratamiento farmacológico , Anomalías Múltiples/genética , Diarrea/congénito , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/genética , Receptores de Enterotoxina/antagonistas & inhibidores , Anomalías Múltiples/metabolismo , GMP Cíclico/metabolismo , Diarrea/tratamiento farmacológico , Diarrea/genética , Diarrea/metabolismo , Mutación con Ganancia de Función , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Errores Innatos del Metabolismo/metabolismo , Receptores de Enterotoxina/genéticaRESUMEN
The etiology of secondary 3-methylglutaconic aciduria (3-MGA-uria) is not well understood although is thought to be a marker of mitochondrial dysfunction. For this reason, suspicion for a secondary 3-MGA-uria often leads to an extensive clinical and laboratory work-up for mitochondrial disease, although in many cases evidence for mitochondrial dysfunction is never found. 3-methylglutaconic aciduria in healthy individuals without known metabolic disease has not been well described. Here, we describe clinical and biochemical features of 23 individuals evaluated at the Greenwood Genetic Center for low plasma free carnitine reported on newborn screening. Of the 23 individuals evaluated, four individuals were diagnosed with primary carnitine deficiency, 16 were identified as carriers for primary carnitine deficiency, and three individuals were determined to be unaffected non-carriers based on molecular and biochemical testing. Elevated 3-MGA (>20 mmol/mol of creatinine) was identified in nine carriers of primary carnitine deficiency, while all unaffected non carriers and all affected individuals with primary carnitine deficiency had a normal 3-MGA level (<20 mmol/mol of creatinine). Average 3-MGA among all carriers was 39.66 mmol/mol of creatinine. Average plasma free carnitine in among all carriers (n = 16) was 13.87 µm/L, and average plasma free carnitine was not significantly different between carriers with and those without elevated 3-MGA (p = 0.66). In summary, we describe elevated 3-MGA as a discriminatory feature in nine healthy carriers of primary carnitine deficiency. Our findings suggest that heterozygosity for pathogenic alterations on SLC22A5 should be considered in the differential for individuals with persistent 3-MGA-uria of unclear etiology.
Asunto(s)
Cardiomiopatías/metabolismo , Carnitina/deficiencia , Carnitina/metabolismo , Hiperamonemia/metabolismo , Errores Innatos del Metabolismo/metabolismo , Enfermedades Musculares/metabolismo , Adulto , Femenino , Heterocigoto , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Mitocondriales/metabolismo , Tamizaje Neonatal/métodos , Miembro 5 de la Familia 22 de Transportadores de Solutos/metabolismoRESUMEN
Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.