Browsing by Subject "Barth syndrome"

Now showing 1 - 4 of 4
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    A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice
    (MDPI, 2024-07-27) Snider, Paige L.; Sierra Potchanant, Elizabeth A.; Sun, Zejin; Edwards, Donna M.; Chan, Ka-Kui; Matias, Catalina; Awata, Junya; Sheth, Aditya; Pride, P. Melanie; Payne, R. Mark; Rubart, Michael; Brault, Jeffrey J.; Chin, Michael T.; Nalepa, Grzegorz; Conway, Simon J.; Anatomy, Cell Biology and Physiology, School of Medicine
    Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele (TazPM) that phenocopies BTHS clinical traits. As TazPM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile TazPM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile TazPM hearts. However, adult TazPM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult TazPM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.
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    Role of Tafazzin in Mitochondrial Function, Development and Disease
    (MDPI, 2020-05-23) Chin, Michael T.; Conway, Simon J.; Pediatrics, School of Medicine
    Tafazzin, an enzyme associated with the rare inherited x-linked disorder Barth Syndrome, is a nuclear encoded mitochondrial transacylase that is highly conserved across multiple species and plays an important role in mitochondrial function. Numerous studies have elucidated the mechanisms by which Tafazzin affects mitochondrial function, but its effects on development and susceptibility to adult disease are incompletely understood. The purpose of this review is to highlight previous functional studies across a variety of model organisms, introduce recent studies that show an important role in development, and also to provide an update on the role of Tafazzin in human disease. The profound effects of Tafazzin on cardiac development and adult cardiac homeostasis will be emphasized. These studies underscore the importance of mitochondrial function in cardiac development and disease, and also introduce the concept of Tafazzin as a potential therapeutic modality.
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    The Loss of Tafazzin Transacetylase Activity Is Sufficient to Drive Testicular Infertility
    (MDPI, 2024-11-26) Snider, Paige L.; Sierra Potchanant, Elizabeth A.; Matias, Catalina; Edwards, Donna M.; Brault, Jeffrey J.; Conway, Simon J.; Pediatrics, School of Medicine
    Barth syndrome (BTHS) is a rare, infantile-onset, X-linked mitochondriopathy exhibiting a variable presentation of failure to thrive, growth insufficiency, skeletal myopathy, neutropenia, and heart anomalies due to mitochondrial dysfunction secondary to inherited TAFAZZIN transacetylase mutations. Although not reported in BTHS patients, male infertility is observed in several Tafazzin (Taz) mouse alleles and in a Drosophila mutant. Herein, we examined the male infertility phenotype in a BTHS-patient-derived D75H point-mutant knockin mouse (TazPM) allele that expresses a mutant protein lacking transacetylase activity. Neonatal and adult TazPM testes were hypoplastic, and their epididymis lacked sperm. Histology and biomarker analysis revealed TazPM spermatogenesis is arrested prior to sexual maturation due to an inability to undergo meiosis and the generation of haploid spermatids. Moreover, TazPM testicular mitochondria were found to be structurally abnormal, and there was an elevation of p53-dependent apoptosis within TazPM seminiferous tubules. Immunoblot analysis revealed that TazPM gamete genome integrity was compromised, and both histone γ-H2Ax and Nucleoside diphosphate kinase-5 protein expression were absent in juvenile TazPM testes when compared to controls. We demonstrate that Taz-mediated transacetylase activity is required within mitochondria for normal spermatogenesis, and its absence results in meiotic arrest. We hypothesize that elevated TazPM spermatogonial apoptosis causes azoospermia and complete infertility.
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    What can ATP content tell us about Barth syndrome muscle phenotypes?
    (OAE, 2025) Brault, Jeffrey J.; Conway, Simon J.; Anatomy, Cell Biology and Physiology, School of Medicine
    Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations. BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the energetics of striated muscle in BTHS mitochondriopathy.