Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

PGC-1a

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101752

Synonyms

Historical Background

PGC-1α is the founding member of a small family of transcriptional coactivators that also includes PGC-1β and PRC (PGC-1-related coactivator). The three members of the family share structural features and exert their regulatory action on gene expression by binding and coactivating an overlapping wide range of transcription factors and nuclear receptors. Although each of the PGC-1 coactivators exhibits some specific functional peculiarities, particularly in the cellular context or physiological situation in which they exert their function, the three members of the family are nowadays considered key players in the control of energy metabolism (Villena 2015).

Mouse PGC-1α was cloned in 1998 in the context of a study aimed at unraveling the mechanisms that control the process of adaptive thermogenesis at the transcriptional level in brown adipose tissue (BAT). In contrast to white adipose tissue (WAT), which functions as an energy storage organ, BAT is specialized in the generation of heat to maintain body temperature by a process known as non-shivering adaptive thermogenesis. Studies in the 1980s had led to the identification of uncoupling protein-1 (UCP1) as a brown adipocyte-specific mitochondrial protein responsible of thermogenesis. The studies carried out in the early 1990s on the Ucp1 gene promoter had revealed that UCP1 expression was strongly dependent on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Indeed, PPARγ was able to drive UCP1 expression in brown adipocytes through its binding to a PPARγ/RXR site located in the enhancer region of the Ucp1 gene. However, the fact that PPARγ was essential for the differentiation of both white and brown adipocytes suggested that PPARγ per se could not be the factor that determined whether the thermogenic program was turned on exclusively in brown adipocytes but not in white adipocytes. Consequently, the existence of a PPARγ cofactor that allowed PPARγ-dependent transcription of the Ucp1 gene specifically in the context of brown fat cells was hypothesized. In 1998, using a yeast two-hybrid system based on a mouse brown fat cell cDNA library to identify PPARγ-interacting proteins, the laboratory of B. Spiegelman cloned PGC-1α (Puigserver et al. 1998). Shortly after, in a study aimed at identifying proteins that interact and modulate the transcriptional activity of glucocorticoid receptors, the laboratory led by A. Kralli identified LEM6 (ligand effect modulator 6) as the human homolog of PGC-1α (Knutti et al. 2000). The seminal studies carried by both laboratories demonstrated that the expression of PGC-1α was not restricted to BAT but that it was highly expressed in many other tissues, such as the heart, kidney, skeletal muscle, brain, or liver. This ubiquitous expression, together with its capacity to interact with multiple nuclear receptors in addition to PPARγ, already predicted a broader role for PGC-1α beyond the regulation of thermogenesis in BAT. Subsequent work has indeed confirmed the importance of PGC-1α in the regulation of multiple cellular and physiological processes in response to diverse physiological cues, as it will be discussed in the following sections. Given the fact that most studies have been carried out in rodent models or cells from murine origin, unless otherwise stated, all the data provided here will refer to the mouse form of the PGC-1α protein, mRNA, or gene.

PGC-1α Protein(s) Structure

Structure of Full Length PGC-1α

The main, first-identified, murine form of PGC-1α corresponds to a 797 aa-long polypeptide. As in the other members of the PGC-1 family of transcriptional coactivators, several regions harboring distinct functional domains can be identified in the amino acid sequence of PGC-1α (Fig. 1). The amino-terminal region of PGC-1α contains a highly conserved activation domain, approximately spanning from aa 1 to aa 180 that serves as a docking surface for histone modifying enzymes, such as CREB-binding protein (CBP)/p300 and steroid receptor coactivator-1 (SRC-1). Also within the amino-terminal end, three leucine-rich LXXLL motifs (L1, L2, and L3) have been found to be involved in the interaction of PGC-1α with several hormone nuclear receptors (Figs. 1 and 2). The central region of PGC-1α, from aa 181 to aa 403, contains a negative regulatory domain to which the p160 myb-binding protein (MYBBP1A) binds to repress the transcriptional activity of PGC-1α. Also within this region, a well-conserved motif DHDY has been identified as a binding site for host cell factor (HFC), a transcription factor required for cell cycle progression. Furthermore, the carboxy-terminal region of PGC-1α contains several arginine-serine-rich (RS) regions and a RNA recognition motif (RRM), which are characteristic of proteins involved in mRNA processing and splicing. The presence of RS and RRM motifs confers to PGC-1α the capacity to bind splicing factors and to regulate the processing of nascent mRNAs in vitro (Monsalve et al. 2000). However, the functional relevance of such domains in vivo remains to be defined.
PGC-1a, Fig. 1

Functional domains of PGC-1α. The main structural and functional domains of PGC-1α are schematically depicted. Posttranslational modifications known to regulate PGC-1α transcriptional activity are also indicated

PGC-1a, Fig. 2

Transcription factors and nuclear receptors that interact with PGC-1α. Only the transcriptional regulators that directly bind to DNA and whose physical interaction with PGC-1α has been demonstrated are shown

PGC-1α Isoforms

The mouse Ppargc1a gene is located in chromosome 5, whereas human PGC-1α is encoded by a single gene (PPARGC1A) in chromosome 4. The expression of the mouse gene is controlled by different promoters that give rise to several RNA products, which in turn are subjected to alternative splicing and generate multiple protein isoforms (Martinez-Redondo et al. 2015) (Fig. 3). The murine 797 aa PGC-1α protein originally described, which originates by the transcription of the Ppargc1a gene from the proximal promoter, is also known as PGC-1α1 or PGC-1α-a, to distinguish it from the newly described forms. Several transcripts that originate from an alternative promoter, also active in humans, located 14 kb upstream of the transcription start site of the proximal promoter have been identified. These transcripts contain a new exon (exon 1b) that, in turn, undergoes differential splicing. The result is the generation of two novel PGC-1α proteins that minimally differ in their amino terminal end: PGC-1α-b, which contains a 12 aa sequence from exon 1b, and PGC-1α-c, which contains a 3 aa amino-terminal end originated from the differential splicing of exon 1b. The functional significance of the subtle differences in the amino-terminal ends of isoforms PGC-1α-a, PGC-1α-b, and PGC-1α-c, if any, remains to be elucidated.
PGC-1a, Fig. 3

PGC-1α isoforms. Differential promoter usage coupled to alternative splicing events results in several functional PGC-1α isoforms

An alternative splicing event between exons 6 and 7 of the mRNAs originated from both the proximal and the alternative promoters introduces a premature stop codon and originates three shorter proteins named NT-PGC-1α-a, NT-PGC1α-b (also known as PGC-1α4), and NT-PGC-1α-c. All of them contain the activation domain and part of the repression domain of the full length PGC-1α-a/b/c forms. Despite losing the carboxy-terminal moiety that contains the RNA processing domains, NT-PGC-1α isoforms retain their transcriptional coactivation activity. Moreover, biological function of these short isoforms considerably overlaps with that of full-length PGC-1α, regulating mitochondrial biogenesis and the expression of genes involved in thermogenesis (i.e., UCP1) (see next sections).

Regulation of PGC-1α Transcriptional Activity

The activity of PGC-1α is finely tuned by multiple posttranslational modifications (Fig. 1) that control the interaction of PGC-1α with transcription factors, nuclear receptors, and chromatin-remodelling complexes (Handschin and Spiegelman 2006).

Phosphorylation

PGC-1α is phosphorylated by different kinases in a variety of physiological contexts. Phosphorylation by p38 mitogen-activated protein kinase (p38 MAPK) at residues T262, S265, and T298 increases PGC-1α stability and, therefore, promotes its cellular accumulation. In addition of increasing its stability, phosphorylation by p38 MAPK also relieves the interaction of PGC-1α with MYBBP1A. Consequently, phosphorylation by p38 MAPK results in a net increase of the intrinsic activity of PGC-1α.

Phosphorylation of PGC-1α at residues T177 and S538 by AMP-activated protein kinase (AMPK) has been described in cultured muscle cells upon stimulation with AICAR, an AMPK activator. Phosphorylation of PGC-1α by AMPK may contribute to enhance PGC-1α-mediated mitochondrial oxidative metabolism in response to exercise and other physiological cues that activate this stress kinase.

PGC-1α is also phosphorylated by glycogen synthase kinase 3β (GSK3β). Phosphorylation by GSK3β favours PGC-1α ubiquitination by the E3 ubiquitin ligase SCFCdc4, leading to its proteolytic degradation. In cultured primary neurons subjected to oxidative stress, the levels of SCFCdc4 are decreased, reducing PGC-1α ubiquitination, increasing its protein levels, and promoting the expression of PGC-1α-target genes encoding for antioxidant proteins.

Negative regulation of gluconeogenesis by insulin has been shown to occur in part through phosphorylation of PGC-1α at S570 by Akt or at S568 and S572 by S6 kinase-1 (S6 K1), both of which inhibit PGC-1α transcriptional activity by preventing its recruitment to the promoter of gluconeogenic genes (see section “Regulation of Hepatic Gluconeogenesis”).

Acetylation

PGC-1α activity is also modulated by the balance between acetylation and deacetylation. Acetylation of PGC-1α is carried out by GCN5 in, at least, 13 lysine residues. Acetylation not only inhibits PGC-1α intrinsic transcriptional activity but also prevents its binding to target gene promoters by inducing its translocation to inactive chromatin domains. Contrarily, deacetylation by sirtuin 1 (SIRT1) activates PGC-1α transcriptional activity. Deacetylation of PGC-1α by SIRT1 depends on its prior phosphorylation by AMPK, indicating that different posttranslational modifications converge to regulate PGC-1α transcriptional activity in a coordinated manner in response to similar physiological stimuli.

Methylation

Methylation by protein arginine methyltransferase 1 (PRMT1) in arginine residues of a RERQR sequence found in the carboxy-terminal region has been shown to activate the transcriptional activity of PGC-1α in vitro. The physiological implications of such modification remain to be defined. However, it has been recently demonstrated in vivo that reduced methylation of hepatic PGC-1α leads to impaired expression of genes involved in fatty acid oxidation, as the result of the decreased interaction of hypomethylated PGC-1α with the nuclear receptors hepatocyte nuclear factor 4α (HNF4α), PPARα, and estrogen-related receptor α (ERRα).

PGC-1α as a Key Regulator of Mitochondrial Biogenesis and Oxidative Metabolism

Control of Mitochondrial Gene Expression and Mitochondrial Biogenesis by PGC-1α

PGC-1α is best known for its role in the regulation of mitochondrial biogenesis. Consistent with this function, PGC-1α is abundantly expressed in tissues with high-energy requirements, such as the heart, skeletal muscle, BAT, or brain. PGC-1α controls the expression of genes involved in almost every aspect of mitochondrial function. This includes genes encoding for proteins of the respiratory chain/oxidative phosphorylation (OxPhos) system, the tricarboxylic acid cycle, the fatty acid β-oxidation, the synthesis of phospholipids and genes related to the import/export of mitochondrial proteins. Moreover, PGC-1α also controls the expression of the machinery required for the transcription and replication of the mitochondrial genome (mtDNA). By this means, PGC-1α ensures the coordinated expression of mitochondrial proteins encoded by both the nuclear and the mitochondrial genomes. For this control over the numerous gene networks involved in mitochondrial architecture and function, PGC-1α is considered as the master regulator of mitochondrial biogenesis.

Both in vitro and in vivo studies have provided evidences that support a crucial role of PGC-1α in the process of mitochondrial biogenesis. Initial studies in cultured cells showed that ectopic overexpression of PGC-1α in adipocytes or muscle cells is sufficient to increase the expression of mitochondrial OxPhos genes, augment mitochondrial mass, and boost oxygen consumption (Puigserver et al. 1998; Wu et al. 1999). In vivo experiments using mouse models in which PGC-1α was overexpressed in a tissue-specific manner led to similar conclusions. For instance, transgenic expression of PGC-1α in skeletal muscle results in a dramatic increase in the expression of mitochondrial genes and oxidative metabolism, which physiologically translates into resistance to contraction fatigue. Similarly, studies using cardiac-specific mouse models of overexpression showed that PGC-1α is also a powerful driver of mitochondrial biogenesis in cardiac cells, dramatically increasing mitochondrial mass in cardiomyocytes.

The studies in rodent models devoid of PGC-1α also confirmed that this coactivator is necessary for the normal expression of mitochondrial genes in a variety of tissues. Yet, the reduction in the expression of mitochondrial genes found in tissues of the PGC-1α systemic or tissue-specific knockout mice is, in general, quite mild. Nevertheless, the moderate reduction of mitochondrial gene expression in mice devoid of PGC-1α is sufficient to decrease oxidative metabolism in muscle and to lead to intolerance to exercise. This, together with the fact that PGC-1α expression is highly induced in skeletal muscle in response to muscle contraction, suggests that PGC-1α is essential for muscle cells to adapt to the high-energy requirements imposed by exercise. Similarly, mice devoid of PGC-1α show a modest decrease in the expression of mitochondrial genes in BAT. However, despite the reduction in gene expression, the mouse models devoid of PGC-1α do not show any significant alteration in mitochondrial mass or morphology. The relatively mild phenotype related to mitochondrial oxidative capacity exhibited by PGC-1α knockout mice together with the fact that mitochondrial mass is not substantially altered in the absence of PGC-1α does not undermine the crucial role of PGC-1α in the control of mitochondrial biogenesis but highlights the existence of redundant mechanisms aimed at maintaining mitochondrial mass and function. In this regard, other members of the PGC-1 family of coactivators, particularly PGC-1β, functionally overlap with PGC-1α in most tissues, ensuring the maintenance of adequate mitochondrial mass in the absence of PGC-1α (Villena 2015).

Mechanisms Involved in the Control of PGC-1α-Dependent Mitochondrial Gene Expression

PGC-1α regulates mitochondrial biogenesis by interacting with a very well-defined set of transcriptional regulators, which includes nuclear respiratory factors (NRF), ERRs, and PPARs (Hock and Kralli 2009).

PGC-1α coactivation of NRF-2 exclusively regulates the expression of OxPhos genes. This also includes the expression of genes encoding for mitochondrial transcription factors A (TFAM) and B (TFBM), which are essential for the replication and transcription of mtDNA. By this means, the tandem PGC-1α/NRF-2 ensures the coordinated expression of proteins of the OxPhos system encoded by both the nuclear and the mitochondrial genomes, increasing the oxidative capacity of mitochondria without the need of increasing mitochondrial mass. NRF-1, a transcription factor that, besides having a similar name, is not related to NRF-2, regulates the expression of a very similar repertoire of genes, including the OxPhos genes and those involved in the transcription and replication of mtDNA. In addition, NRF-1 regulates genes encoding for proteins that participate in the import and assembly of mitochondrial proteins, as well as genes involved in the synthesis of the heme group, all of which are essential for proper mitochondrial oxidative function.

PGC-1α also binds and coactivates members of the PPAR family of nuclear receptors. The interaction with PPARα and PPARδ results in the control of a very specific network of mitochondrial genes engaged in lipid catabolism, including lipid uptake, transport, and β-oxidation. The activation of PPARα and PPARδ by specific ligands and its subsequent coactivation by PGC-1α allow the cell to rapidly adapt to situations in which fatty acids are the dominant substrate for ATP production, as it occurs during fasting.

Furthermore, PGC-1α exerts its transcriptional control over the entire process of mitochondrial biogenesis by interacting with the three members of the ERR family of orphan nuclear receptors (ERRα, ERRβ, and ERRγ). ERRs, which appear to be functionally redundant, bind to specific regulatory sites located in the promoters of genes involved in every single aspect of mitochondrial function and activate their transcription. These networks include genes of the OxPhos system, the tricarboxylic acid cycle, and the fatty acid oxidation, but also genes involved in mitochondrial dynamics (fusion/fission), protein import and assembly, and replication and transcription of mtDNA. Therefore, the interaction of PGC-1α with ERRs ensures the integral control of mitochondrial biogenesis by simultaneously activating the expression of all the genes required to make fully functional mitochondria.

Tissue-Specific Functions of PGC-1α

Beyond the control of mitochondrial gene expression in most tissues and cell types, PGC-1α controls several other cellular and physiological processes in a tissue-specific manner. The most important and best documented of such tissue-specific PGC-1α functions are described below.

Regulation of Non-shivering Adaptive Thermogenesis in Brown Adipose Tissue

Control of non-shivering adaptive thermogenesis (NST) was the first function attributed to PGC-1α. NST consists in the production of heat by specialized cells, the brown adipocytes, to maintain body temperature in response to cold exposure (Cannon and Nedergaard 2004). The thermogenic function of brown adipocytes relies on uncoupling protein-1 (UCP1), a brown adipocyte-specific protein located in the inner membrane of mitochondria. UCP1 acts as a proton channel that provides a direct path for the protons accumulated in the intermembrane mitochondrial space by the activity of the respiratory chain toward the mitochondrial matrix, bypassing the ATP synthase complex. As a result, the energy associated to the proton electrochemical gradient is dissipated as heat instead of being used for the production of ATP.

The expression and activity of UCP1 is dramatically increased in response to low environmental temperatures to fulfill the thermogenic requirements of the organism. The control of UCP1 expression in response to adrenergic stimulation is entirely dependent on PGC-1α and involves an increase in PGC-1α protein levels and posttranslational modifications that boost PGC-1α transcriptional activity. The mechanisms underlying the increase in the expression of PGC-1α in response to adrenergic stimulation involve ATF2 (activating transcription factor 2), which upon phosphorylation by p38 MAPK binds to a cAMP-response element (CRE) located in the proximal region of the Ppargc1a gene promoter to facilitate its transcription. In addition of increasing PGC-1α expression, activation of p38 MAPK by cold results in the phosphorylation of PGC-1α, leading to the stabilization of the protein. Therefore, the final result of adrenergic stimulation is a net increase in the amount of active PGC-1α, which interacts with several transcription factors (PPARγ/α; TRβ, thyroid hormone receptor β; and RARα, retinoic acid receptor alpha) bound to the Ucp1 promoter region to induce UCP1 expression and facilitate NST. The short NT-PGC-1α isoforms are also induced by cold exposure and similarly drive the expression of the thermogenic program in response to β3-adrenergic stimulation (Chang et al. 2012). Interestingly, cold exposure induces the expression of the PGC-1α isoforms transcribed from the alternative promoter (PGC-1α-b, PGC-1α-c, NT-PGC-1α-b, and NT-PGC-1α-c), while the isoforms expressed under basal conditions (PGC-1α-a and NT-PGC-1α-a) are expressed from the proximal promoter.

The essential role of PGC-1α in the regulation of NST has been unequivocally demonstrated by using PGC-1α knockout mouse models. Mice lacking both the full length and the short NT-PGC-1α isoforms exhibit severe cold intolerance when acutely exposed to low environmental temperatures as a result of the failure to properly increase UCP1 expression and mount an adequate thermogenic response (Lin et al. 2004). However, mice devoid only of full-length PGC-1α isoforms, but that retain the expression of NT-PGC-1α forms, can normally defend their body temperature upon exposure to cold (Chang et al. 2012). This indicates that the NT-PGC-1α forms retain the relevant structural and functional features that allow them to interact with transcription factors present in the Ucp1 promoter and positively regulate UCP1 expression in response to adrenergic stimulation.

Regulation of Hepatic Gluconeogenesis

In addition of regulating mitochondrial gene expression, liver PGC-1α is key in the regulation of gluconeogenesis in response to fasting. The control of PGC-1α over the hepatic gluconeogenic process is achieved through the interaction with transcription factors like HNF4α, forkhead box O1 (FoxO1), cAMP-response element binding protein (CREB), and glucocorticoid receptors (GR) that directly bind to specific sites in the promoter regions of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc).

In response to fasting, the expression of PGC-1α is highly induced in hepatocytes by the effect of glucagon, catecholamines, and glucocorticoids. The action of glucagon and catecholamines leads to a raise in the cytoplasmic concentration of cAMP, which results in the activation of protein kinase A and the subsequent phosphorylation of CREB. In turn, CREB binds to consensus CRE sites on the Ppargc1a gene promoter and increases PGC-1α expression.

Posttranslation modifications of PGC-1α are also crucial for the regulation of gluconeogenesis during the fasting/refeeding cycles. In response to fasting, PGC-1α is deacetylated by SIRT1, a NAD+-dependent deacetylase whose expression and activity is induced in response to nutrient deprivation. Deacetylation of PGC-1α increases its transcriptional activity, leading to the specific expression of genes involved in gluconeogenesis and fatty acid oxidation, without affecting the transcription of other mitochondrial genes. Analogously, in fed conditions, PGC1α is acetylated by the acyltransferase GCN5, repressing PGC-1α transcriptional activity. Simultaneously, nutrient and insulin activation of S6K1 and Akt leads to the phosphorylation of PGC-1α at inhibitory residues, contributing to the negative regulation of gluconeogenesis during the fed state. Hepatic S6K1-mediated phosphorylation of PGC-1α specifically affects the expression of gluconeogenic genes by preventing its interaction with HNF4α, but it does not affect the expression of mitochondrial genes, to whose promoters PGC-1α stills binds through the interaction with ERRα and PPARα.

Supporting an important role of PGC-1α in the control of hepatic gluconeogenesis, ectopic overexpression of PGC-1α in mouse liver or in cultured hepatocytes induces the expression of gluconeogenic genes and enhances glucose production (Yoon et al. 2001). Consistently, fasted PGC-1α knockout mice exhibit a mild hypoglycemia up and fail to raise glucose concentration in blood after an injection of gluconeogenic substrates, such as pyruvate. Moreover, hepatocytes derived from PGC-1α knockout mice fail to normally increase the expression of gluconeogenic genes in response to hormonal treatment that mimic the fasting state (Lin et al. 2004).

Regulation of Skeletal Muscle Angiogenesis by PGC-1α

The expression of PGC-1α is also highly induced in skeletal muscle in response to exercise, leading to the generally accepted notion that PGC-1α plays an essential role on the adaptations of muscle cells to exercise. The use of mouse models that ectopically overexpress PGC-1α provided evidences supporting this view. For instance, muscle-specific PGC-1α transgenic mice exhibit increased mitochondrial gene expression and oxidative capacity. In addition, PGC-1α overexpression promotes angiogenesis and enhances the conversion of fast-twitch low-oxidative muscle fibers into slow-twitch high-oxidative myofibers. However, the use of PGC-1α knockout mice has revealed that the coactivator is not required to increase mitochondrial gene expression and mass in response to exercise or for fiber-type conversion. However, it has been demonstrated in vivo that PGC-1α mediates angiogenesis in response to hypoxia and exercise by regulating the expression of vascular endothelial growth factor (VEGF) in an ERRα-dependent manner (Arany et al. 2008; Chinsomboon et al. 2009).

Summary

PGC-1α appears as a versatile transcriptional coactivator that regulates multiple genetic programs in a tissue- and cue-specific manner (Fig. 4). Besides its ubiquitous role as a regulator of mitochondrial biogenesis by controlling the expression of all the genes required for making functional mitochondrial, PGC-1α has been found to regulate very specific processes in a tissue-dependent manner. Of those, the regulation of hepatic gluconeogenesis in response to fasting and brown adipose tissue thermogenesis in response to low environmental temperatures is without a doubt the best characterized. Of note, PGC-1α appears to have a more relevant role in extreme situations to which the organisms need to rapidly adapt in order to thrive, such as nutrient deprivation, low temperature, or exercise. For this reason, PGC-1α expression not only is highly induced in response to these cues but also its transcriptional activity is enhanced by multiple posttranslational modifications. The studies carried out in cellular or genetically engineered animal models have implicated PGC-1α in the control of several other functions, such as fiber-type specification and hypertrophy in skeletal muscle, phospholipid synthesis in heart, control of oxidative stress in neural tissues, or proliferation and differentiation of hematopoietic cells (Villena 2015). However, further research is needed in order to clarify to which extent PGC-1α is truly important in the control of these processes in vivo.
PGC-1a, Fig. 4

Main functions of PGC-1α. The major functions of PGC-1α for which solid experimental evidences have been provided both in vitro and in vivo are summarized

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of Metabolism and ObesityVall d’Hebron – Institut de Recerca, Universitat Autònoma de BarcelonaBarcelonaSpain
  2. 2.CIBER on Diabetes and Associated Metabolic Diseases (CIBERDEM)MadridSpain