Peroxisome Proliferator–Activated Receptor γ Coactivator-1 (PGC-1) Regulatory Cascade in Cardiac Physiology and Disease

The constant workload of the heart requires a high-capacity mitochondrial system to match ATP production with functional demands. In the adult mammalian heart, ATP synthesis occurs primarily through complete oxidation of fatty acids and glucose in the mitochondrion. Mitochondrial metabolic pathways are exquisitely regulated at many levels. Mitochondrial oxidative flux is modulated by concentrations of substrates and metabolite intermediates and by posttranslational modification of enzymes catalyzing key, rate-limiting reactions. Importantly, the capacity for mitochondrial oxidative energy metabolism also is regulated at the level of gene transcription. The present review summarizes recent work that defines the role of a transcriptional coactivator, peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), as a master regulator of myocardial energy metabolism in diverse physiological and pathophysiological conditions.The mitochondrion is an efficient ATP synthesis machine that rapidly converts energy stored in fatty acids, glucose, and lactate into high-energy phosphates, which provide the fuel driving contractile function, ion homeostasis, and other cellular processes within the cardiac myocyte. Fatty acids enter the mitochondrion intact and are catabolized in the mitochondrial fatty acid β-oxidation spiral. Oxidation of fatty acids in this pathway produces reducing equivalents (NADH and FADH2) and acetyl-CoA, a 2-carbon molecule that can enter the tricarboxylic acid cycle for further oxidation (Figure 1). For glucose to enter the oxidative pathways of the mitochondrion, it must first undergo anaerobic metabolism in the cytosol of the cardiac myocyte and be converted to pyruvate (Figure 1). This 3-carbon intermediate can then be converted to lactate outside the mitochondrion or oxidized in the mitochondrial matrix to generate acetyl-CoA for the tricarboxylic acid cycle. Oxidation of acetyl-CoA in the tricarboxylic acid cycle produces NADH and FADH2, which carry electrons to the electron transport chain. The electron transport chain then produces ATP through the process of oxidative phosphorylation (OXPHOS). The ATP …