Cardiolipin remodeling--role in mitochondrial function

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DESCRIPTION (provided by applicant): The mitochondrion is central for pathways of ATP production, the synthesis and degradation of metabolites, lipid metabolism, and iron-sulfur cluster assembly. Mitochondrial dysfunction contributes to a broad range of neural and muscular diseases including cardiomyopathy and neutropenia associated with the X-linked disease Barth Syndrome, which is categorized as a rare disorder. Barth syndrome is caused by mutations in the gene tafazzin (Taz1) which functions as a putative cardiolipin acyltransferase in the mitochondrion. Cardiolipin is a specific lipid found in the mitochondria! inner membrane and defects in cardiolipin maintenance have been linked to aging and apoptosis. The goals of this proposal are to (1) investigate the function of Taz1p by determining its localization within mitochondria and subsequent biogenesis and (2), using yeast as a model, identify small molecule effectors that affect cardiolipin remodeling. Taz1p biogenesis studies will pinpoint the location within the mitochondrion and provide a platform for understanding the mechanism by which small molecule effectors may modulate cardiolipin assembly. Small molecule effectors from chemical libraries will be identified using a high-throughput screen with yeast mutants deleted for proteins in the cardiolipin assembly pathway. The organism that will serve as a model is the budding yeast Saccharomyces cerevisiae because it is genetically and biochemically tractable and many aspects of mitochondrial physiology are similar between fungi and animals. The long-term goal of this research program is to develop tools for studying mitochondrial lipid biogenesis in the heart because this is an understudied pathway. The identification of small molecule effectors should in theory lead to the development of new tools to investigate lipid assembly and trafficking pathways and potentially lay the groundwork for the development of novel therapeutics. These tools will then be applied to mammalian systems such as cultured cardiomyocytes. This application has a broader impact in public health because cardiac disease affects the general population. The mitochondrion is required for energy production in the heart and defects in cardiolipin assembly and maintenance can lead to cardiac dysfunction. The development of new tools for studying cardiolipin assembly has the potential to lead to the development of therapeutics for cardiac dysfunction and will lead to a better understanding of how the heart cell functions.