PGC-1: REGULATOR OF MITOCHONDRIAL METABOLISM IN HEART

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The adult mammalian heart utilizes fatty acids as its predominant energy source. In hypertrophy, the heart switches from fatty acid oxidation (FAO) to glucose metabolism for energy generation. The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates expression of genes encoding key FAO enzymes, FFARalpha is a nuclear receptor transcription factor that functions with co-activator proteins to activate transcription. The recently identified co-activator, PPAR gamma co- activator-1 (PGC-1), is a candidate for cooperating with PPARalpha to regulate FAO enzyme genes. Both proteins are down-regulated during cardiac hypertrophy, implicating a role for PPARalpha/PGC-1 signaling in the hypertrophy gene program. PGC-1 has also been shown to regulate genes involved in mitochondrial biogenesis by a mechanism independent of its function with PPARalpha. The specific aims are to 1) characterize the role of PPARalpha and its, co-activator, PGC-1, in the control of cardiac mitochondrial energy transduction pathways, 2) co-activator, PGC-1, in the control of cardiac mitochondrial energy transduction pathways, 3) map functional domains within the PGC-1 molecular relevant to the development of dominant inhibitory mutants, and 3) determine whether PPARalpha/PGC-1 signaling plays a primary role in the cardiac myocyte hypertrophy program. Long-term goals involve development of genetically engineered animals to investigate the roles of PGC-1 in regulating cardiac metabolism in vivo.