A major discovery for the study of metabolism occurred when deciphering the galactose operon in bacteria. It revealed how organisms can adapt their metabolic activity to environmental changes modifying the expression levels of metabolic enzymes. Furthermore, it showed for the first time a link between enzymatic activity modulation and transcriptional control of gene expression 66.
Transcriptional control of metabolism requires specific signals to be transduced to the cell nucleus where defined sets of genes are targeted. Although virtually all transcription factors (TFs) are involved in metabolic regulation, few of them have been shown to play a predominant role in it. Particularly, nuclear receptors act as metabolic sensors that when activated, bind to specific response elements located in the vicinity of the promoter of their target genes, being responsible for the metabolic adaptation66. Among them is it worth to mention the following ones: the Peroxisome Proliferator
Activated Receptors (PPARs)67, which are nuclear, lipid-sensing molecules that control genes involved
in lipid metabolism; the Hepatic Nuclear Factor 4α (HNF4α)68; the retinoid X receptor (RXRs)69, which
act as active heterodimers with metabolic sensor nuclear receptors (except for HNF4α); Sterol Regulatory Element Binding Proteins (SREBP)70, Liver X Receptor (LXR)71, Farnesol X Receptors
(FXR)72, which are closely involved in cholesterol metabolism; and finally, CCAAT/enhancer-binding
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IN TR OD U C TI ONbeen identified as a physiological and functional endogenous agonist of the estrogen-related receptor α (ERRα), therefore, this TF could also be included in the aforementioned list74.
Importantly, in the last years the interest has also been focused on transcriptional co-factors that regulate the transcriptional activity of TFs. Therefore, they have emerged as crucial regulators to fine-tune many homeostatic processes75. Among many metabolic co-regulators (Fig I10), an extensive
body of literature has highlighted the relevance of the peroxisome proliferator-activate receptor coactivator 1α (PGC1α) and Sirtuin 1(SIRT1) in mitochondrial function and metabolism regulation. Because of this, recent research has focused the attention in this additional layer of physiological control and has augmented the awareness to define the regulatory roles of these co-regulators in homeostasis and physiology75.
Figure I 10.Metabolic co-regulator protein families Representation of the 23 major co-regulators involved in
metabolic regulation ((PGC1A, HDAC1, HDAC9, HDAC3, KAT2A, NCOR2, NRIP1, CRTC3, PGC1B, NCOA2,
CRTC2, MED1, NCOA3, NCOA1, KAT2B, HDAC7, NCOR1, HDAC4, RB1, SIRT1, HDAC5, CRTC1 and HDAC2).
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IN TR OD U C TI ONIV.1.1 PGC1 co-regulator family
The PGC1 co-regulator family comprises three different members PGC1α, PGC1β and PGC- related coactivator (PRC). Of these members, PGC1α was the first described and is the most highly regulated among them. Initially, PGC1α was discovered as an interacting partner of PPARγ in brown adipose tissue, driving mitochondrial biogenesis and thermogenesis under cold exposure76. PGC1α is
a 798-amino acid protein that is encoded by the PPARGC1A gene located on human chromosome 4. Up to ten different isoforms have been found for PGC1α, which shared a high level of similarity, but differ in the modulation of functions across tissue types77. PGC1β and PRC were identified by sequence
homology with PGC1α and share functional similarities regulating mitochondrial biogenesis and metabolism78,79.
Collectively, all the three PGC1 co-regulator family members act like docking platforms for assembly of the transcription machinery, orchestrating the functions of transcription factors, chromatin- modifying complexes, and transcription initiators that act in concert to drive target gene expression80.
All the members present an activation domain at the N terminus containing the nuclear receptor coactivator motif LXXLL, which recruits protein complexes that facilitate transcription, such as histone acetyltransferases (CBP/p300 and SRC1). Furthermore, a proline-rich domain divides two distinct regions for nuclear respiratory factor 1 (NRF1) binding. Preceding the C terminus there is an interaction domain for the Mediator complex (thyroid receptor-associated protein/vitamin D receptor-interacting protein complex TRAP/DRIP) that mediates transcription initiation.This region is also thought to recruit the SWI/SNF chromatin remodelling complex, thus providing another level of transcriptional activation. Finally, the C-terminal region presents an Arginine/Serine-rich domain and a RNA recognition motif, which can couple pre-mRNA splicing with transcription80,81.
The presence of leucine-rich motifs in the protein surface allow this members to interact with different nuclear receptors or transcription factors, including NRF1/2, GABP, PPARs, ERRs and YY1. Among their actions, which are tissue and transcription factor-specific, they control mitochondrial biogenesis and remodelling, expression of muscle contractile proteins, hepatic gluconeogenesis, lipoprotein metabolism, circadian metabolic rhythm, reactive oxygen species (ROS) detoxification and angiogenesis81,82. Due to their capacity to promote mitochondrial biogenesis, improve oxidative
metabolism and antioxidant responses, they are highly expressed in energy-demanding tissues, such as heart, skeletal muscle, brown fat, brain and kidney82,83. Importantly, the nuclear receptor
corepressor receptor-interacting protein 140 (RIP140) acts as a brake on mitochondrial biogenesis, being the antithesis of PGC1 co-regulators. It can bind to different nuclear receptor (including ERRs and PPARs) via LXXLL motifs, similar to PGC1 co-regulators81 (Fig I11). According to the results
obtained in this thesis work, we have focused our attention in PGC1α co-regulator and its binding to ERRα, and the function they exert regulating mitochondrial biogenesis and metabolism.
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IN TR OD U C TI ONV Metabolic deregulation and cancer
The first evidence reporting a reprogramming of cell metabolism was provided by Otto Warburg almost a century ago84. This German pioneer physiologist demonstrated that tumour cells
consume massive amounts of glucose to produce lactate through aerobic glycolysis, even being exposed to ambient oxygen85. Nonetheless, this discovery was left aside for many years in cancer
research until recently, when cancer metabolism become a topic of renewed interest. Aided by new biochemical and molecular tools, studies in cell metabolism have expanded our understanding of mechanisms and functional consequences of tumour-associated metabolic alterations. The consolidation of this field has led to the determination of metabolic rewiring in cancer as a hallmark of the disease3.
Figure I 11. PGC1 family functions according to TFs binding. PGC1α is represented in the figure as it is the better characterised among the members of the family, although PGC1β has been shown to play a similar role.