Molecular mechanisms and treatment of cardiomyopathy in Barth Syndrome

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PROJECT SUMMARY Mutations in tafazzin (Taz, also known as G4.5) cause Barth syndrome (BTHS, MIM 302060), a life-threatening disorder disrupting metabolism of the mitochondrial-specific phospholipid cardiolipin (CL). Cardiomyopathy is the major clinical feature in BTHS, highlighting the importance of Taz and the CL metabolism pathway in cardiomyocytes (CMs). Taz encodes a mitochondrial phospholipid-lysophospholipid transacylase, which is essential for CL remodeling to achieve the characteristic fatty acid composition of mature CL. Mutations in Taz found in BTHS patients result in low total CL concentrations, abnormal CL fatty acyl composition, and elevated monolyso-CL (MLCL) to CL ratios. However, little is known as to the detailed molecular mechanisms by which Taz deficiency and consequent CL abnormalities lead to the progression of cardiomyopathy. Thus far, there is no curative therapy for BTHS. Although it has been established that Taz deficiency causes BTHS, lack of a Taz knockout mouse model has hindered studies of molecular pathology and developments of therapeutic approaches for BTHS. To elucidate the molecular pathogenic mechanism of BTHS cardiomyopathy, and to identify potential targets for therapeutic intervention, we have generated Taz CM-specific knockout (cKO) mice and observed dilated cardiomyopathy (DCM) phenotypes, as well as mitochondrial malformations and dysfunction in Taz cKO mice. Our data strongly suggest a critical role of Taz and CL in cardiac and mitochondrial function. Our Taz cKO mouse provides us with a unique model to investigate the molecular basis for and potential therapeutic approaches to BTHS. Studies in cultured cells suggest that linoleic acid (LA) supplementation increases mature CL levels in Taz-deficient cells by increasing incorporation of linoleoyl groups into de novo synthesized CL and also ameliorating the increase in MLCL. Inhibition of the mitochondrial phospholipase A2 (PLA2) by bromoenol lactone (BEL) also ameliorates increased MLCL in Taz-deficient cells by blocking generation of MLCL from nascent CL. However, these potential therapeutic approaches have not been studied in an in vivo mammalian model of BTHS. Moreover, no study has explored if a combination of LA supplementation and BEL treatment can act synergistically to ameliorate BTHS. Accordingly, our hypothesis is that Taz-mediated CL remodeling is essential to maintain mitochondrial homeostasis and CM function, and that linoleic acid (LA) and/or bromoenol lactone (BEL) treatment will provide beneficial effects to ameliorate BTHS cardiomyopathy. Our specific aims are: (1) To investigate the role and molecular mechanisms by which Taz- mediated CL remodeling is required in maintaining CM mitochondrial homeostasis and normal cardiac function by histological, physiological, biochemical, and molecular analyses of Taz cKO mice; and (2) To assess therapeutic effects of linoleic acid (LA) and mitochondrial PLA2 inhibitor bromoenol lactone (BEL), as single agents or in combination, on BTHS cardiomyopathy by utilizing Taz cKO mice.