Myocardial disturbances of intermediary metabolism in Barth syndrome.
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ABSTRACT:
SUBMITTER: Greenwell AA
PROVIDER: S-EPMC9399503 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Myocardial disturbances of intermediary metabolism in Barth syndrome.
Greenwell Amanda A AA Tabatabaei Dakhili Seyed Amirhossein SA Ussher John R JR
Frontiers in cardiovascular medicine 20220810
Barth Syndrome (BTHS) is a rare X-linked mitochondrial disorder due to mutations in the gene <i>TAFAZZIN</i>, which leads to immature cardiolipin (CL) remodeling and is characterized by the development of cardiomyopathy. The immature CL remodeling in BTHS results in electron transport chain respiratory defects and destabilization of supercomplexes, thereby impairing ATP production. Thus, BTHS-related cardiomyopathy appears to share metabolic characteristics of the failing heart being an "engine ...[more]
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Project description:Barth syndrome (BTHS) is an X-linked recessive disorder that is typically characterized by cardiomyopathy (CMP), skeletal myopathy, growth retardation, neutropenia, and increased urinary levels of 3-methylglutaconic acid (3-MGCA). There may be a wide variability of phenotypes amongst BTHS patients with some exhibiting some or all of these findings. BTHS was first described as a disease of the mitochondria resulting in neutropenia as well as skeletal and cardiac myopathies. Over the past few years, a greater understanding of BTHS has developed related to the underlying genetic mechanisms responsible for the disease. Mutations in the TAZ gene on chromosome Xq28, also known as G4.5, are responsible for the BTHS phenotype resulting in a loss-of-function in the protein product tafazzin. Clinical management of BTHS has also seen improvement. Patients with neutropenia are susceptible to life-threatening bacterial infections with sepsis being a significant concern for possible morbidity and mortality. Increasingly, BTHS patients are suffering from heart failure secondary to their CMP. Left ventricular noncompaction (LVNC) and dilated CMP are the most common cardiac phenotypes reported and can lead to symptoms of heart failure as well as ventricular arrhythmias. Expanded treatment options for end-stage myocardial dysfunction now offer an opportunity to change the natural history for these patients. Herein, we will provide a current review of the genetic and molecular basis of BTHS, the clinical features and management of BTHS, and potential future directions for therapeutic strategies.
| S-EPMC3892174 | biostudies-literature
Project description:BackgroundBarth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function.Methods/resultsYoung adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g-1·min-1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g-1·min-1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS.ConclusionsMyocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.
| S-EPMC7205570 | biostudies-literature
Project description:First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
| S-EPMC3583704 | biostudies-other
Project description:Barth syndrome (BTHS) is an X-linked recessive multisystem disorder caused by mutations in the TAZ gene (TAZ, G 4.5, OMIM 300394) that encodes for the acyltransferase tafazzin. This protein is highly expressed in the heart and plays a significant role in cardiolipin biosynthesis. Heart disease is the major clinical manifestation of BTHS with a high incidence in early life. Although the genetic basis of BTHS and tetralinoleoyl cardiolipin deficiency in BTHS-affected individuals are well-established, downstream metabolic changes in cardiac metabolism are still uncovered. Our study aimed to characterize TAZ-induced metabolic perturbations in the heart. Control (PGP1-TAZWT) and TAZ mutant (PGP1-TAZ517delG) iPS-CM were incubated with 13C6-glucose and 13C5-glutamine and incorporation of 13C into downstream Krebs cycle intermediates was traced. Our data reveal that TAZ517delG induces accumulation of cellular long chain acylcarnitines and overexpression of fatty acid binding protein (FABP4). We also demonstrate that TAZ517delG induces metabolic alterations in pathways related to energy production as reflected by high glucose uptake, an increase in glycolytic lactate production and a decrease in palmitate uptake. Moreover, despite mitochondrial dysfunction, in the absence of glucose and fatty acids, TAZ517delG-iPS-CM can use glutamine as a carbon source to replenish the Krebs cycle.
| S-EPMC6950123 | biostudies-literature
Project description:Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.
| S-EPMC10628049 | biostudies-literature
Project description:Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.
2023-11-15 | GSE247576 | GEO
Project description:Barth syndrome (BTHS) is a rare multisystemic genetic disorder caused by mutations in the TAZ gene. TAZ encodes a mitochondrial enzyme that remodels the acyl chain composition of newly synthesized cardiolipin, a phospholipid unique to mitochondrial membranes. The clinical abnormalities observed in BTHS patients are caused by perturbations in various mitochondrial functions that rely on remodeled cardiolipin. However, the contribution of different cardiolipin-dependent mitochondrial functions to the pathology of BTHS is not fully understood. In this review, we will discuss recent findings from different genetic models of BTHS, including the yeast model of cardiolipin deficiency that has uncovered the specific in vivo roles of cardiolipin in mitochondrial respiratory chain biogenesis, bioenergetics, intermediary metabolism, mitochondrial dynamics, and quality control. We will also describe findings from higher eukaryotic models of BTHS that highlight a link between cardiolipin-dependent mitochondrial function and its impact on tissue and organ function. © 2019 IUBMB Life, 9999(9999):1-11, 2019.
| S-EPMC6586490 | biostudies-literature
Project description:Objectives: Barth syndrome is an ultra-rare, infantile-onset, X-linked recessive mitochondrial disorder, primarily affecting males, due to variants in TAZ encoding for the cardiolipin transacylase tafazzin. This review aimed to summarize and discuss recent and earlier findings concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and outcome of Barth syndrome. Method: A literature review was undertaken through a MEDLINE search. Results: The phenotype of Barth syndrome is highly variable but most frequently patients present with hypertrophic/dilated/non-compaction cardiomyopathy, fibroelastosis, arrhythmias, neutropenia, mitochondrial myopathy, growth retardation, dysmorphism, cognitive impairment, and other, rarer features. Lactic acid and creatine kinase, and blood and urine organic acids, particularly 3-methylglutaconic acid and monolysocardiolipin, are often elevated. Cardiolipin is decreased. Biochemical investigations may show decreased activity of various respiratory chain complexes. The diagnosis is confirmed by documentation of a causative TAZ variant. Treatment is symptomatic and directed toward treating heart failure, arrhythmias, neutropenia, and mitochondrial myopathy. Conclusions: Although Barth syndrome is still an orphan disease, with fewer than 200 cases described so far, there is extensive ongoing research with regard to its pathomechanism and new therapeutic approaches. Although most of these approaches are still experimental, it can be expected that causative strategies will be developed in the near future.
| S-EPMC6558240 | biostudies-literature
Project description:IntroductionBarth syndrome (BTHS) is a rare X-linked disorder characterized by cardiomyopathy, neutropenia, growth abnormalities, and skeletal myopathy. There have been few studies investigating health-related quality of life (HRQoL) in this population. This study investigated the impact of BTHS on HRQoL and select physiologic measures in affected boys and men.MethodsIn this study, we characterize HRQoL in boys and men with BTHS through cross-sectional analysis of a variety of outcome measures including the Pediatric Quality of Life Inventory (PedsQLTM) Version 4.0 Generic Core Scales, PedsQLTM Multidimensional Fatigue Scale, Barth Syndrome Symptom Assessment, the PROMISTM Fatigue Short Form, the EuroQol Group EQ-5DTM, the Patient Global Impression of Symptoms (PGIS), and the Caregiver Global Impression of Symptoms (CaGIS). For a specific subset of participants, physiologic data were available in addition to HRQoL data.ResultsFor the PedsQLTM questionnaires, 18 unique child and parent reports were analyzed for children aged 5-18 years, and nine unique parent reports were analyzed for children aged 2-4 years. For the other HRQoL outcome measures and physiologic measurements, the data from 12 subjects (age range 12-35 years) were analyzed. Based on parent and child reports, HRQoL is significantly impaired in boys and men with BTHS, especially in school functioning and physical functioning. Parent and child reports of more severe fatigue are significantly correlated with more impaired HRQoL. When exploring the potential relationship between physiology and HRQoL, the CaGIS as a whole for pediatric subjects and individual questionnaire items from the PGIS and CaGIS for pediatric subjects assessing tiredness, muscle weakness, and muscle pain showed the strongest correlations.ConclusionThis study provides a unique characterization of the HRQoL in boys and men with BTHS using a variety of outcome measures, and it highlights the negative impact of fatigue and muscle weakness on HRQoL in BTHS.Trial registry nameA Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects with Barth Syndrome (TAZPOWER). https://clinicaltrials.gov/ct2/show/NCT03098797.Registration Number: NCT03098797.
| S-EPMC10032447 | biostudies-literature
Project description:Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.
| S-EPMC9537754 | biostudies-literature