Cardiac Mitochondrial Biogenesis in Health and Disease

The heart has an amazing capacity for ATP production by burning tremendous quantities of fat and glucose in mitochondria. The high capacity mitochondrial system in heart develops as a late developmental event, during the perinatal stages. This mitochondrial biogenic response involves a switch towards greater reliance on fatty acid oxidation as the chief source of ATP along with a robust increase in mitochondrial number and function. We are interested in defining the gene regulatory circuitry involved in this cardiac metabolic maturation. We also seek to determine whether this program becomes dysregulated in common disease states leading to heart failure. The results of our studies have led us to determine that the transcriptional coactivator PGC-1{alpha} and its downstream transcription factor targets including the nuclear receptors , estrogen-related receptors (ERR) and peroxisome proliferator-activated receptors (PPAR), are critically involved in the postnatal metabolic maturation of the heart. In common forms of cardiac hypertrophy and heart failure caused by hypertension and ischemia, this program becomes downregulated causing a shift towards a “fetal” phenotype. In the diabetic heart, chronic activation of the PGC-1{alpha}/PPAR{alpha} circuit leads to myocardial lipid metabolic derangements referred to as “lipotoxicity”. Studies aimed at defining the roles of this cascade in normal mitochondrial biogenesis and in myocardial disease pathogenesis using gain-of-function and loss-of-function genetically modified mice will be presented.