This application is directed towards understanding the mechanisms involved in pathogenesis of Barth syndrome, a rare X-linked mitochondrial disorder, caused by mutations in the tafazzin (taz) gene and characterized by dilated cardiomyopathy, skeletal myopathy, chronic fatigue, exercise intolerance, cyclic neutropenia and organic aciduria. The taz gene encodes a mitochondrial protein with a high degree of homology to acyl-transferases. Mutations in taz gene result in reduction of cardiolipin, a tetraphospholipid, and accumulation of monolysocardiolipins (MLCL) in mitochondria, a diversification of cardiolipin species, which are normally dominated by tetra-linoleoyl cardiolipin (L4CL). Taz function has been studied in non-mammalian model organisms, such as yeast, flies and zebrafish. Although existing models of taz-deficiency provide valuable information about the role of taz in CL metabolism and mitochondrial function, these systems cannot be adequately used and manipulated to study the long range effects of gene deletion or mutation in the whole organism and do not allow development and testing of potential therapies. Therefore, we generated an inducible taz-knockdown mouse model by employing RNA- interference technology. We ascertained the efficiency of taz-silencing and analyzed its consequences, which we hypothesized would impact cardiac function and to alter the mitochondria of cardiac and skeletal muscles. Taz deficiency caused aberrant CL molecular speciation, reduction of L4CL and accumulation of MLCL in heart and skeletal muscle. Moreover taz deficiency resulted in severe cardiac malfunction, with ultrastructural defects and excessive autophagy in sarcomeric tissues. Based on our preliminary studies, we hypothesize that L4CL is essential for mitochondrial energy production, mitochondrial structural integrity, and cross-communication of mitochondria with other intracellular organelles. To explore our hypothesis, we propose three Specific Aims: (i) to characterize the detailed cardiac and skeletal muscle phenotype of the mouse tafazzin deficiency, (ii) To assess the extent of the permanent damage caused by cardiolipin deficiency and to estimate how much of this damage is reversible, (iii) To investigate mechanisms by which taz-deficiency impairs mitochondrial function. PUBLIC HEALTH RELEVANCE: The grant proposal entitled "A mouse model of Barth syndrome, a mitochondrial cardiolipin disorder " is designed to study molecular mechanisms of pathogenesis of Barth syndrome, a rare genetic pediatric disorder, caused by mutations in the tafazzin gene. We will utilize our newly-developed mouse model for tafazzin deficiency. We believe that the proposed study will define the roles of cardiolipin in mitochondrial function and will enable the development of efficient therapeutic strategies to treat Barth patients and related syndromes.