Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS). Individuals with this X-linked multisystem disorder present cardiomyopathy (CM) (often dilated), skeletal muscle weakness, neutropenia, growth retardation, and 3-methylglutaconic aciduria. Biopsies of the heart, liver and skeletal muscle of patients have revealed mitochondrial malformations and dysfunctions. It is the purpose of this review to summarize recent results of studies on various animal or cell models of Barth syndrome, which have characterized biochemically the strong cellular defects associated with TAZ mutations. Tafazzin is a mitochondrial phospholipidlysophospholipid transacylase that shuttles acyl groups between phospholipids and regulates the remodeling of cardiolipin (CL), a unique inner mitochondrial membrane phospholipid dimer consisting of two phosphatidyl residues linked by a glycerol bridge. After their biosynthesis, the acyl chains of CLs may be modified in remodeling processes involving up to three different enzymes. Their characteristic acyl chain composition depends on the function of tafazzin, although the enzyme itself surprisingly lacks acyl specificity. CLs are crucial for correct mitochondrial structure and function. In addition to their function in the basic mitochondrial function of ATP production, CLs play essential roles in cardiac function, apoptosis, autophagy, cell cycle regulation and Fe-S cluster biosynthesis. Recent developments in tafazzin research have provided strong insights into the link between mitochondrial dysfunction and the production of reactive oxygen species (ROS). An important tool has been the generation of BTHS-specific induced pluripotent stem cells (iPSCs) from BTHS patients. In a complementary approach, disease-specific mutations have been introduced into wild-type iPSC lines enabling direct comparison with isogenic controls. iPSC-derived cardiomyocytes were then characterized using biochemical and classical bioenergetic approaches. The cells are tested in a "heart-on-chip" assay to model the pathophysiology in vitro, to characterize the underlying mechanism of BTHS deriving from TAZ mutations, mitochondrial deficiencies and ROS production and leading to tissue defects, and to evaluate potential therapies with the use of mitochondrially targeted antioxidants.
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PMID:Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies. 2683 81

Cardiolipin (CL) is a mitochondrial phospholipid that helps maintain normal structure of the inner mitochondrial membrane and stabilize the protein complexes of the electron transport chain to promote efficient ATP synthesis. Tafazzin, an acyl-transferase, is required for synthesis of the mature form of CL. Mutations in the tafazzin (TAZ) gene are associated with a human disorder known as Barth syndrome. Symptoms of Barth syndrome often include muscle weakness and exercise intolerance. Previous work demonstrates that Drosophila Taz mutants exhibit motor weakness, as measured by reduced flying and climbing abilities. However, Drosophila TAZ mutants' baseline endurance or response to endurance exercise training has not been assessed. Here, we find that TAZ mutants have reduced endurance and do not improve following a stereotypical exercise training paradigm, indicating that loss of TAZ function leads to exercise intolerance in Drosophila. Although cardiac phenotypes are observed in human Barth syndrome patients, TAZ mutants had normal resistance to cardiac pacing. In the future, endurance may be a useful screening tool to identify additional genetic modifiers of tafazzin.
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PMID:Drosophila tafazzin mutants have impaired exercise capacity. 2940 56

Tafazzin is a mitochondrial enzyme that exchanges fatty acids between phospholipids by phospholipid-lysophospholipid transacylation. The reaction alters the molecular species composition and, as a result, the physical properties of lipids. In vivo, the most important substrate of tafazzin is the mitochondria-specific lipid cardiolipin. Tafazzin mutations cause the human disease Barth syndrome, which presents with cardiomyopathy, skeletal muscle weakness, fatigue, and other symptoms, probably all related to mitochondrial dysfunction. The reason why mitochondria require tafazzin is still not known, but recent evidence suggests that tafazzin may lower the energy cost associated with protein crowding in the inner mitochondrial membrane.
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PMID:The Function of Tafazzin, a Mitochondrial Phospholipid-Lysophospholipid Acyltransferase. 3223 10