PGC1Alpha Pathway
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PGC1Alpha Pathway
PGC1Alpha (Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1-Alpha) is a tissue-specific transcriptional coactivator that enhances the activity of many nuclear receptors and coordinates transcriptional programs important for cellular energy metabolism and overall energy homeostasis (Ref.1). It is a key regulator of cardiac mitochondrial functional capacity and participates in the transduction of physiologic stimuli to energy production in the heart. The expression of the PGC1Alpha gene is upregulated after birth in the heart, before the known increase in mitochondrial biogenesis and switch from glucose to fatty acids as the chief energy substrate. PGC1Alpha gene expression is activated by short-term fasting, a condition known to increase cardiac mitochondrial FAO (Fatty Acid Oxidation) rates. Moreover, cardiac-specific overexpression of PGC1Alpha is sufficient to induce mitochondrial biogenesis (Ref.2) and coupled oxygen consumption, implicating this transcriptional coactivator in the regulation of mitochondrial respiration and thus, ATP production (Ref.3).

PGC1Alpha is predominantly expressed in mitochondrial-rich tissues such as heart, brown adipose tissue, skeletal muscle, and to some extent liver, tissues with high energy demands (Ref.4). It has been implicated in mitochondrial biogenesis in the heart and skeletal muscle; fatty acid Beta-oxidation, adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscles (Ref.1). Its expression is induced in a tissue-specific manner by physiological stimuli that relay metabolic needs. Exposure to cold leads to the induction of PGC1Alpha in brown adipose tissue and muscle, starvation induces its expression in heart and liver, and physical exercise increases its expression in heart and skeletal muscle (Ref.5). Conversely, pressure overload, diets rich simultaneously in saturated fats and carbohydrates, certain inflammatory molecules and oxidants are the negative factors that decrease PGC1Alpha expression (Ref.6). Cells sense energy charge by responding to the concentration of ATP versus ADP and AMP. Exercise improves muscle respiratory capacity by inducing mitochondrial proliferation. Exercise induces PGC1Alpha through CalmKIV (Calcium/Calmodulin-Dependent Protein Kinase- IV) and, secondarily, through AMPK (AMP-activated Protein Kinase). During muscle contraction ATP levels drop, leading to a relative increase in ADP and AMP. AMP activates the AMPK. In turn, AMPK mediates contraction-stimulated glucose transport in muscle. This occurs through an Insulin-independent pathway that involves translocation of the GLUT4 (Glucose Transporter-4) to the plasma membrane. AMPK induces expression of PGC1Alpha, but the dominant effect of exercise on PGC1Alpha is through CalmKIV (Ref.7). Exercise and subsequently elevated intracellular Calcium levels result in an activation of both CalmKIV and Calcineurin in skeletal muscle. Activated CalmKIV can phosphorylate CREB (cAMP Response Element-Binding Protein) and NFAT (Nuclear Factor of Activated T-Cell), which then increases transcription of PGC1Alpha via a conserved CREB-binding site in the proximal promoter (Ref.8).

Transcription factors that guide PGC1Alpha action to specific genes include nuclear receptors, members of other transcription factor families, such as NRF1 (Nuclear Respiratory Factor-1), which controls the expression of mitochondrial proteins, and MEF2s (Myocyte Enhancer Factor-2) (Ref.2). They recruit PGC1Alpha to the promoters of target genes that execute its metabolic effects (Ref.5). These combinatorial interactions upregulate the expression of fatty acid oxidation, oxidative phosphorylation, and tricarboxylic acid cycle enzymes as well as uncoupling proteins in response to cold, fasting, or exercise. Calcineurin and CalmK signaling activate the transcriptional activity of MEF2s in part by promoting the dissociation of inhibitory HDACs (Histone Deacetylases). CalmK stimulates phosphorylation of class II HDACs, leading to their export from the nucleus. MEF2 activity is repressed by class II HDACs, which dissociate from MEF2 when phosphorylated on two serine residues in response to calcium signaling. Inactivation of HDAC5 (Histone Deacetylase-5) by CalmKIV or related kinases derepress PGC1Alpha expression, resulting in increased mitochondrial biogenesis (Ref.2). MEF2 binds to at least one MEF2-binding site in the PGC1Alpha flanking region and increases transcriptional activity. Newly synthesized PGC1Alpha protein can coactivate MEF2s and thus positively regulate its own transcription (Ref.8). The Calcineurin and CalmK-signaling pathways also induce the transformation of fast glycolytic skeletal muscle fibers to slow oxidative fibers, accompanied by the up-regulation of PGC1Alpha in an MEF2-dependent manner (Ref.2).

The heart has an extraordinarily high capacity for mitochondrial ATP production to meet the rigorous and dynamic energy demands of the postnatal environment. PGC1Alpha is also implicated in the transcriptional control of mitochondrial biogenesis during adaptive thermogenesis through its interaction with NRF1 (Ref.4). As mitochondria contain proteins encoded by both nuclear and mitochondrial genes, mitochondrial biogenesis requires the coordinate regulation of these 2 genomes. The transcriptional regulatory network controlling the expression of nuclear and mitochondrial genes includes NRF1 and TFAM (Transcription Factor-A Mitochondrial). PGC1Alpha activates expression of NRF1 target genes directly by coactivating NRF1 and indirectly by upregulating expression of the NRF1 gene and its targets. NRF1 activates the expression of known target genes, including mtTFA, a factor that is critical for the transcription of mtDNA genes and the initiation of mitochondrial DNA replication (Ref.6). Both basal and Insulin-stimulated glucose transport are increased by ectopic expression of PGC1Alpha. PGC1Alpha physically interacts with MEF2C (Myocyte Enhancer Factor-2C) to upregulate GLUT4 expression, its recruitment to the plasma membrane and glucose uptake. Cytokine activation of the p38MAPK pathway results in phosphorylation of PGC1Alpha with a concomitant increase in the activity of the protein (Ref.1), but in high concentrations, MAPK inactivates the IRS by phosphorylation of a serine residue, which in turn impairs GLUT4 activation, glucose transport into cells and may explain the mechanism of Insulin insensitivity. Reduced expression of PGC1Alpha and inefficient glucose oxidation might lead to spillover of glucose into the glucosamine pathway. Glucosamine can also downregulate mitochondrial respiratory genes (Ref.7).

PGC1Alpha exerts its actions through PPAR-Alpha (Peroxisome Proliferative Activated Receptor-Alpha), which in turn modulate the expression of PPREs (PPAR Response Elements) - genes coding for key enzymes involved in glucose and fatty acid oxidation (Ref.9). As fatty acid oxidation is entirely dependent on mitochondrial respiration and glucose oxidation can occur anaerobically, attenuated mitochondrial respiration will have a greater effect on fatty acid oxidation. Accumulation of fatty Acyl-CoA causes Insulin resistance (Ref.7). ERR-Alpha (Estrogen-Related Receptor-Alpha), also acts as an effector of PGC1Alpha, and it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR-Alpha compromises the ability of PGC1Alpha to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content (Ref.10). Overexpression of PGC1Alpha in the heart enhances mitochondrial biogenesis. Conversely, down-regulation of PGC1Alpha expression results in a loss of cardiac mitochondria (Ref.2). However, inappropriate increases in PGC1Alpha activity have been linked to a number of pathological conditions including heart failure and diabetes mellitus (Ref.1). PGC1Alpha mRNA levels are increased in both type-1 and type-2 diabetes and may contribute to elevated hepatic glucose production in diabetic states. Inborn errors in mitochondrial FAO enzymes and mutations of the mitochondrial genome are now recognized as important causes of cardiomyopathy, metabolic disturbances, and skeletal myopathy in pediatric and adult populations. Common acquired cardiac diseases are also associated with mitochondrial functional abnormalities. Mitochondrial DNA deletions occur with aging and in the ischemic heart. Mitochondrial DNA mutations, which lead to abnormalities in oxidative phosphorylation, cause a variety of diseases, including cardiomyopathy, neuromuscular dysfunction, and diabetes mellitus (Ref.3). Considering the wide range of pathophysiologic states in which the PGC1Alpha regulatory pathway is involved, PGC1Alpha would appear to be an attractive therapeutic target for a number of conditions including heart failure and diabetes that have an underlying metabolic component.