PGC-1 coactivators in cardiac development and disease

Abstract

The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last 10 years have seen a resurgent interest in cardiac intermediary metabolism and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-γ coactivator (PGC)-1 family of proteins plays a central role in these pathways. The mechanisms by which PGC-1 proteins regulate transcriptional networks and are regulated by physiological cues, as well as the roles they play in cardiac development and disease, are reviewed here.

Figure 1. A.) Schematic of regulation of gene expression by PGC-1 coactivators

PGC-1 binds directly to transcription factors and serves as a docking scaffold for histone modifying enzymes, TRAP/DRIP/Mediator complex and RNA splicing machinery. B.) The PGC-1 family of coactivators. PGC1 family members share significant primary sequence homology in their activation and RNA binding domains, as well as domain organization.

Figure 1. A.) Schematic of regulation of gene expression by PGC-1 coactivators

PGC-1 binds directly to transcription factors and serves as a docking scaffold for histone modifying enzymes, TRAP/DRIP/Mediator complex and RNA splicing machinery. B.) The PGC-1 family of coactivators. PGC1 family members share significant primary sequence homology in their activation and RNA binding domains, as well as domain organization.

Figure 2. Transcriptional networks and regulation of PGC-1α

Multiple stimuli activate PGC-1, leading to the coactivation of key transcription factors involved in fatty-acid oxidation and import, angiogenesis, electron transport chain assembly, membrane biogenesis, and mitochondrial DNA replication and transcription.

Figure 3. Substrate utilization in the heart, and metabolic enzymes induced by PGC-1α

Neonatal rat ventricular myocytes (NRVM) were infected with adenovirus expressing PGC-1α versus GFP control, and 48hrs later gene expression was measured by qPCR. Metabolic pathways are noted in green. Induced genes are noted in red boxes. Glucose transporter 4 (GLUT4), hexokinase (HK), glucosephosphate isomerase (GPI), phosphofructose kinase (PFK), aldoase A (ALDA), triosephosphate isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPD), phosphoglycerate mutase (PGAM),enolase (ENO), glycogen synthase (GYS), lactate dehydrogenase (LDH), monocarboxylic acid transporter (MCT), pyruvate dehydrogenase (PDH), aconitase (ACO), citrate synthase (CS), isocitrate dehydrogenase (IDH), alpha-ketoglutarate dehydrogenase (OGDH), succinate-CoA-ligase (SUCL), succinate dehydrogenase (SDH), fumarase (FH), malate dehydrogenase (MDH), 3-alpha-hydroxybutyrate dehydrogenase (BDH), acetyl-CoA acetyltransferase (ACAT), medium-chain acyl-CoA dehydrogenase (MCAD), short-chain acyl-CoA dehydrogenase (SCAD), very long-chain acyl-CoA dehydrogenase (VLCAD), fatty-acid translocase (CD36), fatty-acid transport protein (FATP), fatty-acid binding protein (FABP), diacylglycerol O-acyltransferase (DGAT), carnitine palmitoyltransferase (CPT), carnitine translocase (CT), adenine nucleotide translocator (ANT), complex I (I), complex II (II), complex III (III), complex IV (IV), complex V (V), medium-chain fatty acid (MCFA), long-chain fatty acid (LCFA).

Figure 4. Coregulation of mitogenesis and vasculogenesis

Vessels provide a constant supply of glucose, oxygen and fatty acids which are metabolized to produce ATP as an energy source. Net 2 ATP via anaerobic glycolysis and lactate production per glucose molecule or 30 ATP per molecule of glucose via oxidative consumption within the mitochondria. Catabolism of long chain fatty-acids such as palmitate within the mitochondria can yield 104 ATP per molecule.