Mitochondrial dysfunction leads to cardiac hypertrophy and failure. Because most proteins localized to mitochondria are nuclear encoded, mitochondrial biogenesis requires protein import. Mammalian studies are currently examining this process, and we have demonstrated cardiac expression for an import protein, DDP2/Timm8b. The knockout dies during heart development. Also, a mouse heterozygous for an OM component, Tom20, develops hypertrophic cardiomyopathy. I propose to examine mitochondrial import and heart development in an alternative model, the zebrafish. Mitochondrial biogenesis is essential for cardiac development, and zebrafish is ideal for rapid assessment of heart defects. To connect mitochondrial import to cardiac disease, I propose the following: (1) to identify the expression of mitochondrial import proteins; (2) to alter the levels of these proteins to generate cardiac phenotypes; and (3) to develop transgenic strains for chemical screens to find novel compounds which affect mitochondrial biogenesis. My proposed studies will serve as a bridge to apply mechanistic studies from yeast to developmental studies in vertebrates, thereby demonstrating the link between mitochondrial biogenesis and cardiac development and disease. ? ? ?
