Barth syndrome is a hereditary cardiomyopathy that also affects skeletal muscles, growth, and neutrophils. The mutated gene (tafazzin) is homologous to a conserved family of phospholipid acyltransferases. Children with Barth syndrome are deficient in the mitochondrial phospholipid cardiolipin, suggesting that the primary defect of the disease may indeed be found in phospholipid metabolism and may specifically affect the phospholipids of mitochondria. We want to study the mechanism by which tafazzin mutation causes cardiomyopathy and skeletal muscle disease. First, we want to identify the enzymatic function of tafazzin. We will identify the intracellular localization of tafazzin, its impact on lipid composition, and its mechanism of action. Second, we want to examine the effect of tafazzin on structure and function of mitochondria. Since mitochondrial dysfunction is a plausible etiology of cardiomyopathy and skeletal muscle weakness, we will analyze mitochondrial ultrastructure and oxidative phosphorylation in cell lines with tafazzin deletion. Third, we want to explore a Drosophila model of Barth syndrome, which was created in our laboratory. We will study lipid metabolism, muscle physiology, morphology, and mitochondrial ultrastructure in fruit flies with tafazzin deletion. The Drosophila model will also be used for cardiac studies since flies contain a contractile fluid pumping organ that shares conserved features of cardiogenesis with all heart-forming creatures, including humans. The project will provide insight into the pathologic mechanism of a unique disease, which presents a novel pathway from lipid defect(s) to cardio-skeletal myopathy. Such information may be useful for the development of new therapeutic approaches to cardiomyopathy and skeletal muscle disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL078788-01A1
Application #
7028570
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Pearson, Gail D
Project Start
2006-01-01
Project End
2009-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$338,000
Indirect Cost
Name
New York University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Schlame, Michael; Acehan, Devrim; Berno, Bob et al. (2012) The physical state of lipid substrates provides transacylation specificity for tafazzin. Nat Chem Biol 8:862-9
Acehan, Devrim; Malhotra, Ashim; Xu, Yang et al. (2011) Cardiolipin affects the supramolecular organization of ATP synthase in mitochondria. Biophys J 100:2184-92
Schlame, Michael; Ren, Mindong (2009) The role of cardiolipin in the structural organization of mitochondrial membranes. Biochim Biophys Acta 1788:2080-3
Acehan, Devrim; Khuchua, Zaza; Houtkooper, Riekelt H et al. (2009) Distinct effects of tafazzin deletion in differentiated and undifferentiated mitochondria. Mitochondrion 9:86-95
Schlame, Michael (2009) Formation of molecular species of mitochondrial cardiolipin 2. A mathematical model of pattern formation by phospholipid transacylation. Biochim Biophys Acta 1791:321-5
Xu, Yang; Zhang, Shali; Malhotra, Ashim et al. (2009) Characterization of tafazzin splice variants from humans and fruit flies. J Biol Chem 284:29230-9
Malhotra, Ashim; Edelman-Novemsky, Irit; Xu, Yang et al. (2009) Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome. Proc Natl Acad Sci U S A 106:2337-41
Malhotra, Ashim; Xu, Yang; Ren, Mindong et al. (2009) Formation of molecular species of mitochondrial cardiolipin. 1. A novel transacylation mechanism to shuttle fatty acids between sn-1 and sn-2 positions of multiple phospholipid species. Biochim Biophys Acta 1791:314-20
Schlame, Michael (2008) Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. J Lipid Res 49:1607-20
Acehan, Devrim; Xu, Yang; Stokes, David L et al. (2007) Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography. Lab Invest 87:40-8

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