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Acta Biochimica et Biophysica Sinica Advance Access published February 16, 2011
Acta Biochim Biophys Sin (2011): 1 – 10 | ª The Author 2011. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmr007.
PGC-1 coactivators in the control of energy metabolism 1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210046, China2Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA*Correspondence address. Tel: þ86-25-85891870 (C.L.)/þ1-734-615-3512 (J.L.); Fax: þ86-25-85891870(C.L.)/þ1-734-615-0495 (J.L.);E-mail: changliu@njnu.edu.cn (C.L.)/jdlin@umich.edu (J.L.) Chronic disruption of energy balance, where energy in the year 2000 will carry a significant lifetime risk of intake exceeds expenditure, is a major risk factor for the developing type 2 diabetes, and therefore become prone to development of metabolic syndrome. The latter is charac- premature cardiovascular disease, blindness, kidney failure, terized by a constellation of symptoms including obesity, and amputations. A cardinal feature of metabolic syndrome dyslipidemia, insulin resistance, hypertension, and non- is severe obesity, which arises from chronic imbalance alcoholic fatty liver disease. Altered expression of genes between energy intake and energy consumption. As such, involved in glucose and lipid metabolism as well as mito- restoration of the energy balance is a major strategy for the chondrial oxidative phosphorylation has been implicated therapy of metabolic disease including obesity, diabetes, in the pathogenesis of these disorders. The peroxisome hypertension, atherosclerosis, and fatty liver diseases.
proliferator-activated receptor g coactivator-1 (PGC-1) Peroxisome proliferator-activated receptor (PPAR) g family of transcriptional coactivators is emerging as a coactivator-1 (PGC-1) family members are multifunctional hub linking nutritional and hormonal signals and energy transcriptional coregulators that act as ‘molecular switches’ metabolism. PGC-1a and PGC-1b are highly responsive in many metabolic pathways. PGC-1a and PGC-1b have to environmental cues and coordinate metabolic gene pro- been shown to regulate adaptive thermogenesis, mitochon- grams through interaction with transcription factors and drial biogenesis, glucose/fatty-acid metabolism, peripheral chromatin-remodeling proteins. PGC-1a has been impli- circadian clock, fiber-type switching in skeletal muscle, cated in the pathogenic conditions including obesity, and heart development. Their versatile actions are achieved type 2 diabetes, neurodegeneration, and cardiomyopathy, by interacting with different transcription factors in a whereas PGC-1b plays an important role in plasma tissue-specific manner. The potent effects of PGC-1 coacti- lipoprotein homeostasis and serves as a hepatic target for vators in coordinating various metabolic processes under- niacin, a potent hypotriglyceridemic drug. Here, we score their significant role in the control of energy review recent advances in the identification of physiologi- metabolism as well as their potential as targets for pharma- cal and pathophysiological contexts involving PGC-1 coactivators, and also discuss their implications for thera-peutic development.
The PGC-1a gene is located on chromosome 5 in mice(chromosome 4 in humans) and encodes a protein contain- ing 797 (mouse) or 798 (human) amino acids ].
Structural and functional studies have indicated thatPGC-1a has a strong transcriptional activation domain at the N terminus, which interacts with several histone acetyl-transferase (HAT) complexes including 3’-5’-cyclic adeno- The prevalence of contemporary life style, characterized by sine monophosphate (cAMP) response element-binding increased consumption of high-fat, high-fructose food and protein (CREB)-binding protein, p300, and steroid receptor reduced physical activity, has driven a dramatic increase in coactivator-1 ]. These proteins acetylate histones and the incidence of metabolic syndrome. It has been projected remodel chromatin structure into a state that is permissive that, by 2025, one in every three American children born for transcriptional activation. Adjacent to the N-terminal PGC-1 coactivators in the control of energy metabolism domain is a regulatory region that roughly spans 200 energy demand, including the BAT, heart, skeletal muscle, amino acids. Toward the C terminus, PGC-1a recruits the kidney, and brain – In fact, when ectopically thyroid receptor-associated protein/vitamin D receptor- expressed in fat or muscle cells, PGC-1a strongly stimu- interacting protein/mediator complex that facilitates direct lates the program of nuclear and mitochondrial-encoded interaction with the transcription initiation machinery [].
mitochondrial genes as well as organelle biogenesis [].
This region also interacts with the switch/sucrose non- The stimulatory effects of PGC-1a on mitochondrial genes fermentable (SWI/SNF) chromatin-remodeling complex are achieved through its coactivation of nuclear respiratory through its interaction with BAF60a The Ser/Arg-rich factors 1 and 2 (NRF1 and NRF2, respectively) and the domain and an RNA-binding domain toward C terminus estrogen-related receptor a (ERRa) [The induc- have been demonstrated to couple pre-mRNA splicing with tion of NRF1 and NRF2 subsequently leads to the transcription ]. As such, PGC-1a serves as a platform for increased expression of mitochondrial transcription factor the recruitment and assembly of various chromatin- A (mtTFA) [as well as other mitochondrial subunits of remodeling and histone-modifying enzymes to alter local the electron transport chain complex such as b-adenosine- chromatin state. Importantly, the PGC-1a transcriptional triphosphate (ATP) synthase, cytochrome c, and cyto- activator complex is also able to displace repressor pro- chrome oxidase IV []. mtTFA translocates to mito- teins, such as histone deacetylase and small heterodimer chondrial matrix, where it stimulates mitochondrial DNA partner, on its target promoters, providing an alternative replication and mitochondrial gene expression mechanism for gene activation [PGC-1a and PGC-1b As mentioned above, a critical aspect of PGC-1a is share extensive domain similarity and several clusters of that it is highly versatile and has the ability to increase conserved amino acids, such as the LXXLL motif that the transcriptional activity of many nuclear receptor interacts with nuclear receptors and host cell factor 1 inter- families, including members of the estrogen, PPAR, reti- noid X, mineralocorticoid, glucocorticoid (GR), liver X (PGC-1-related coactivator), also contains the activation (LXR), pregnane X, the constitutive androstane, vitamin domain and RNA-binding domain, but overall has more limited homology to PGC-1a and PGC-1b []. The PGC-1 PGC-1a can also bind to unliganded nuclear receptors, family members are conserved in higher vertebrates, as in the case of the orphan hepatic nuclear factor including mammals, birds, and fish. Interestingly, a PGC-1 (HNF) 4a, farnesoid X receptor (FXR), and ERRa, family homologue named Spargel was recently identified suggesting that their conformations are conductive to in Drosophila that could regulate mitochondrial activity ligand-independent mechanisms of gene regulation [].
PGC-1a transcriptional partners are not limited to the Both PGC-1a and PGC-1b robustly regulate mitochon- nuclear receptor superfamily; however, this coactivator drial oxidative metabolism (Fig. ). PGC-1a was initially also associates with a diverse array of other transcription identified as a PPARg-interacting protein from the brown factors, including forkhead/winged helix protein family adipose tissue (BAT) that could regulate adaptive thermo- member FOXO1, as well as a number of zinc-finger pro- genesis in response to cold []. Subsequent studies revealed that the core function of PGC-1a was to stimulate screen ]. The docking interface for these interacting proteins appears to distribute throughout the length of PGC-1a is abundantly expressed in tissues with high PGC-1a. In addition, PGC-1a has three functional Figure 1 The working model of PGC-1 coactivators PGC-1a and PGC-1b regulate diverse metabolic programs through coactivating selective transcriptional factors (TF) associated with regulatory elements of target genes. PGC-1 recruits HAT, SWI/SNF chromatin-remodeling, Sirt1 deacetylase,and mediator complexes to modulate the epigenetic status of chromatin.
PGC-1 coactivators in the control of energy metabolism LXXLL motifs that are responsible for docking nuclear PGC-1a function by repressing its transcription [].
Impaired PGC-1a expression and mitochondrial function proteins enables PGC-1a to regulate various metabolic contributes to neurodegeneration in susceptible neurons processes in a tissue-specific manner.
In addition, PGC-1a plays an important role in theregulation of genes responsible for the detoxification of Tissue-specific metabolic actions of PGC-1 reactive oxygen species (ROS), including copper/zinc superoxide dismutase (SOD1), manganese SOD (SOD2),and glutathione peroxidase 1 ]. In this case, PGC-1a The following section reviews PGC-1 functions in oxi- protects dopaminergic neurons from degeneration caused dative tissues including the brain, heart, brown fat, skeletal by oxidative stress. Taken together, the finding that muscle, liver, and pancreatic islets, based on gain and PGC-1a expression is impaired in the striatum of HD loss-of-function analysis both in cultured cells and in vivo.
patients raises the possibility that molecules activating A summary of tissue-specific PGC-1 functions and the PGC-1a may be therapeutically useful.
phenotype of PGC-1 transgenic mouse models are includedin and respectively.
Heart is an organ with an extremely high and dynamic demand for ATP. Much of this supply comes from fatty-acid b-oxidation, though glucose also serves as fuel several brain areas, predominantly in the striatum, and source. Several studies have demonstrated that PGC-1a is a exhibit behavioral abnormalities including marked hyper- crucial regulator of oxidative metabolism in the heart.
activity and frequent limb clasping Recent studies PGC-1a mRNA levels are strongly induced in the neonatal heart, along with the activation of mitochondrial biogenesis support a crucial role of this factor in neuronal function and the metabolic switch from glycolysis to oxidative and energy balance. Similar brain lesions are observed phosphorylation in cardiac muscle ]. Overexpression of when PGC-1a is selectively ablated in CaMKIIa-positive PGC-1a both in vitro and in vivo powerfully induces mito- neurons, providing direct evidence for its action in chondrial gene expression and biogenesis ]. PGC-1a neurons. Of note, striatal degeneration with hyperactivity expression is reduced in several animal models of cardiac is reminiscent of Huntington’s disease (HD) in humans, dysfunction, which is typically accompanied by a meta- potentially implicating PGC-1a in the selective vulner- bolic switch from fat oxidation to glycolysis []. PGC-1a ability of striatal neurons in HD. To date, the specific null mice exhibit significantly lower cardiac reserve in role of PGC-1a in linking mitochondrial dysfunction to HD pathogenesis has been explored. The mutant hun- Moreover, PGC-1a null mice develop early symptoms of tingtin protein accumulated in HD brain interferes with heart failure, such as activation of the fetal program of Table 1 Tissue-specific functions of PGC-1a and PGC-1b Maintenance of mitochondrial function ROS detoxification Mitochondrial oxidative metabolism [], fatty-acid b-oxidation Mitochondrial OXPHOS mediating the effects of Mitochondrial biogenesis and fat oxidation [Adaptive Brown adipocyte differentiation []; Adaptive Slow-switch muscle fiber [], mitochondrial biogenesis Hepatic fasting response [], homocysteine metabolism [], integration of circadian clock and metabolism [] Suppression of GSIS and membrane depolarization [] PGC-1 coactivators in the control of energy metabolism Table 2 Phenotypes of PGC-1 knockout and transgenic mouse models Hyperactive, cold-sensitive, resistant to diet-induced obesity, lesions in the Reduced muscle performance and exercise capacity, impaired adaptive Impaired glucose tolerance, normal peripheral insulin sensitivity Switch of type II muscle fiber to type IIa and I muscle fibers, resistance to Loss of sarcomeric structure, dilated cardiomyopathy Increased mitochondrial biogenesis, derangements of mitochondrial ultrastructure, Impaired mitochondrial function, reduced body weight and fat mass, increased thermogenesis, blunted chronotropic response to dobutamine in the heart, hepatic steatosis, reduced lipoprotein-associated triglyceride and cholesterol content Decreased activity during the dark cycle, abnormal hypothermia and morbidity, hepatic steatosis, increased serum triglyceride and cholesterol Mitochondrial dysfunction in liver and skeletal muscle, hepatic steatosis, hepatic Increased fatty-acid oxidation, hyperphagia, reduced body weight and adipose tissue, increased exercise capacity, increased IIX fiber content Neonatal lethality, bradycardia, intermittent heart block, reduced cardiac output, reduced growth, a late fetal arrest in mitochondrial biogenesis cardiac gene expression and a significant increase in circu- lating levels of atrial natriuretic peptide, a hallmark of In rodents, BAT is the major organ responsible for adaptive cardiac dysfunction These mice also exhibit lower thermogenesis during cold exposure. In contrast to white treadmill-running capacity and diminished cardiac function adipose tissue, whose primary physiological function is after exercise. However, it should be noted that superphy- energy storage, the main function of BAT is energy dissi- siological expression of PGC-1a in the heart leads to pation, largely in the form of heat. The expression of robust mitochondrial proliferation and myofibrillar displa- PGC-1a is strongly induced in BAT by cold temperature; cement, and dilated cardiomyopathy ensues [As such, PGC-1a is downstream of the b-adrenergic receptor/cAMP therapeutic regulation of PGC-1a in heart failure should pathway and sympathetic nervous system activity ].
aim at restoring PGC-1a function in cardiac muscle within In this case, PGC-1a turns on several key components a therapeutically beneficial window.
involved in the adaptive thermogenic program, including PGC-1b is also abundantly expressed in the heart [].
the stimulation of fuel uptake, mitochondrial fatty-acid Heart function in PGC-1b-deficient mice is largely unaf- b-oxidation, and stimulation of uncoupling protein 1 fected under normal conditions []. However, PGC-1b (UCP1) expression ]. PGC-1a interacts with other ablation reduces mitochondrial content in cardiac muscle nuclear hormone receptors such as PPARa, retinoic acid and blunts the effect of adrenergic stimulation on heart rate receptor, and thyroid receptor to enhance UCP1 expression.
Remarkably, mice with combined deficiency of PGC-1a and PGC-1b (PGC-1ab2/2) die shortly after birth generating heat and uncouples oxidative phosphorylation with small hearts, bradycardia, intermittent heart block, and from ATP production. PGC-1a-deficient mice are unable a markedly reduced cardiac output Cardiac-specific to defend against cold stress due to thermogenic defects ablation of PGC-1b on a PGC-1a-deficient background results in cardiac defects including reduced growth, a late PGC-1b mRNA is induced during white and brown fetal arrest in mitochondrial biogenesis, and persistence of a adipocyte differentiation ]. Interestingly, while the fetal pattern of gene expression These observations expression of PGC-1b is not cold inducible, its deficiency suggest that PGC-1a and PGC-1b collectively are required also impairs adaptive thermogenesis [], suggesting that for the postnatal metabolic and functional maturation of the these two coactivators play non-redundant function in fuel PGC-1 coactivators in the control of energy metabolism RNAi-mediated liver-specific PGC-1a knockdown mice PGC-1a is abundantly expressed in skeletal muscle, par- display the impairment of gluconeogenic gene expression ticularly slow-twitch myofibers, and is rapidly inducible by and hepatic glucose production []. These mice exercise training in rodents and humans – It is develop hypoglycemia and hepatic steatosis upon fasting clear that calcium signaling pathways play important roles In addition, PGC-1a regulates the genes encoding in the induction of PGC-1a through calcineurin and homocysteine synthesis enzymes in the liver and modulates calcium-dependent protein kinases and the subsequent acti- plasma homocysteine levels ]. Forced expression of vation of CREB and myocyte-enhancing factor 2 ].
PGC-1a in vivo leads to elevated plasma homocysteine In addition, p38 mitogen-activated protein kinase ( p38 MAPK) and AMP-dependent kinase (AMPK) are also In mammals, circadian clock regulates major aspects of required for exercise-induced PGC-1a expression ].
energy metabolism, including glucose and lipid homeosta- Interestingly, muscle-specific overexpression muscle cre- sis and mitochondrial respiration. Our recent work revealed atine kinase (MCK) of PGC-1a in mice turns white, glyco- that PGC-1a is a key component of the circadian oscillator lytic skeletal muscles (fast-twitch muscle fibers) into red, that integrates the peripheral clock and energy metabolism PGC-1a stimulates the expression of Bmal1, a core clock gene, in hepatocytes and muscle cells through coacti- vation of the ROR family of orphan nuclear receptors.
slow-twitch myofibers ]. In addition to the regulation of Mice lacking PGC-1a have abnormal diurnal rhythms of mitochondrial function, PGC-1a increases mRNA content activity, body temperature, and metabolic rate. As PGC-1a of enzymes involved in fat metabolism such as fatty-acid expression is regulated by nutritional and hormonal cues, it translocase/CD36, carnitine palmitoyltransferase I, and is likely that it links these signals to the clockwork and medium-chain acyl-coenzyme A dehydrogenase (MCAD) synchronizes tissue metabolism with circadian pacemaker.
in skeletal muscle [Consistent with the molecular PGC-1b expression is increased in response to dietary changes, PGC-1a transgenic muscle has increased fatigue intake of fats and leads hyperlipidemia through activating resistance following electrical stimulation [In contrast, both whole-body and muscle-specific PGC-1a knock out (VLDL) secretion []. Several factors are involved in med- (KO) mice show reduced mRNA and/or protein content of iating the effects of PGC-1b on plasma triglyceride metab- mitochondrial respiratory chain proteins and ATP synthase.
olism, including sterol response element-binding protein They are exercise intolerant and their skeletal muscles are (SREBP), LXR, and Foxa2 Recent studies demon- strated that PGC-1b and its target gene apolipoprotein C3 In primary cultures of rat muscle cells, PGC-1b (ApoC3) are downstream of nicotinic acid, a widely used increases the expression of glucose transporter 4, myosin hypotriglyceridemic drug []. Both acute injection and heavy chain Ib, and other slow-twitch muscle markers chronic feeding of mice with nicotinic acid suppress While PGC-1b also stimulates mitochondrial biogen- PGC-1b and ApoC3 expression in the liver [These esis in skeletal muscle, it appears to drive a program of studies illustrated a new role for PGC-1b in modulating gene expression that is reminiscent of type IIx fibers [].
lipoprotein catabolism and the relevance of this pathway in In addition, the expression of PGC-1b, but not PGC-1a, is therapeutic action of nicotinic acid. Remarkably, systemic decreased along with reduced ERRa activity and MCAD delivery of antisense oligonucleotide targeting PGC-1b expression in skeletal muscle of senescence-accelerated improved systemic metabolic homeostasis in the model of fructose-induced insulin resistance ].
Hepatic PGC-1a expression reaches its peak during early b-Cell dysfunction is cardinal for the development of type postnatal period []. In adults, starvation induces PGC-1a 2 diabetes. PGC-1a is expressed in pancreatic b-cells and expression in the liver through glucagon and GR signaling is elevated in animal models of type 2 diabetes [].
PGC-1a orchestrates a complex program of metabolic Ectopic expression of PGC-1a impairs both early and changes that occur during the transition of a fed to a fasted delayed glucose-stimulated insulin secretion (GSIS) and liver, including gluconeogenesis, fatty-acid b-oxidation, suppresses membrane depolarization without affecting ketogenesis, heme biosynthesis, and bile-acid homeostasis.
baseline insulin secretion. Altered PGC-1a expression is These effects of PGC-1a on fasting adaption are achieved accompanied by increased glucose-6-phosphatase and by coactivating key hepatic transcription factors, such as reduced glucokinase gene expression. Furthermore, UCP2 HNF4a, PPARa, GR, FOXO1, FXR, and LXR []. In may be another effector downstream of PGC-1; UCP2 accordance with these observations, PGC-1a KO mice and PGC-1 coactivators in the control of energy metabolism production, and negatively regulates GSIS Although the mechanism through which PGC-1a is induced in dia-betic animal models is not understood, fatty acids and As PGC-1a regulates multiple aspects of energy metab- incomplete inactivation of FOXO1 may contribute to olism, it is not surprising that PGC-1a has been found to this process. In contrast to animal data, studies in human be dysregulated in several pathological conditions. The type 2 diabetic islets showed that PGC-1a mRNA expression of PGC-1a and its target genes involved in expression is markedly reduced and correlated with the mitochondrial oxidative phosphorylation (OXPHOS) is sig- reduction in insulin secretion in those islets ]. DNA nificantly decreased in the skeletal muscle of patients with methylation of the PGC-1a gene promoter is increased in type 2 diabetes ]. Similar reduction of PGC-1a human diabetic islets. Therefore, the exact function of expression was also observed in the adipose tissue of PGC-1a in pancreatic islets needs further study.
insulin-resistant and morbidly obese individuals [].
The function of PGC-1b in islets is less studied. A Interestingly, thiozolidinedione, an important class of anti- recent study indicated that PGC-1b, in contrast to PGC-1a, diabetic drugs, can enhance the expression of PGC-1a and directly binds to and acts as a coactivator of SREBPs and mitochondrial biogenesis in white adipose tissue [].
Foxa2 involved in pancreas development and function While these observations support a potentially beneficial The authors also showed that PGC-1b suppresses role of PGC-1a in insulin resistance and type 2 diabetes, GSIS via upregulation of UCP2 and granuphilin gene several studies suggested distinct actions of PGC-1a in other tissues. For example, PGC-1a expression is elevatedin the liver of both type 1 and type 2 diabetic mousemodels ]. Furthermore, PGC-1a has been shown to stimulate hepatic glucose production and suppress b-cell Post-translational modifications of PGC-1 energy metabolism and insulin release in mice [].
Paradoxically, transgenic expression of PGC-1a in skeletalmuscle leads to robust mitochondrial biogenesis but also PGC-1a undergoes extensive post-translational modifi- causes insulin resistance, likely the result of imbalance of cations, including acetylation, phosphorylation, methyl- lipid uptake and oxidation [In addition, a common ation, and SUMOylation, in response to nutritional and polymorphism of the PGC-1a gene (Gly482Ser), which hormonal signals. These modifications allow fine-tuning of apparently reduces PGC-1a activity, has been linked to PGC-1a activities in a context-dependent manner. The acetyl transferase general control of amino-acid synthesis In the cardiovascular system, PGC-1a expression is also 5 acetylates PGC-1a at several lysine residues, alters its decreased in hypertrophic heart ]. PGC-1a null mice localization within the nucleus, and inhibits its transcrip- display accelerated cardiac dysfunction and clinical signs tional activity On the contrary, deacetylation of of heart failure In contrast, PPARa ligand-dependent PGC-1a through sirtuin 1 (Sirt1) increases PGC-1a activity transcriptional activity and coactivation by PGC-1a are on gluconeogenic gene transcription in the liver [].
enhanced in the heart by stress including ischemia and PGC-1a is phosphorylated by both p38 MAPK and AMPK hypoxia ]. In peripheral vessel tissues, downregulation in skeletal muscle [], leading to a more stable and of PGC-1a expression was observed in vascular smooth active protein. In contrast, phosphorylation of PGC-1a by muscle cells (VSMCs) treated by oleic acid and high Akt/protein kinase B downstream of the insulin signaling glucose []. Restoration of PGC-1a has beneficial effects cascade in the liver decreased its stability and transcriptional on VSMCs and endothelial cells ]. In this context, activity []. In addition, PGC-1a also undergoes methyl- PGC-1a appears to play an important role in ROS metab- ation at several arginine residues in the C-terminal region olism and defense against oxidative stress. These obser- by protein arginine methyltransferase 1 ]. Finally, vations indicate that PGC-1a is an important factor in the PGC-1a can undergo SUMOylation in conserved lysine regulation of cardiovascular function.
residue 183 and its transcriptional activity is attenuated Abnormalities in mitochondrial function are associated Interestingly, experiments using C2C12 cells have indi- with neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, and HD. Levels of PGC-1a PGC-1a for deacetylation by Sirt1 [], suggesting that are reduced in the brain of HD patients due to repression different modifications of PGC-1a likely communicate with of PGC-1a gene expression by mutant huntingtin, leading each other to coordinately regulate its activity. PGC-1b is to mitochondrial defects and increased oxidative stress also acetylated at multiple sites however, the biologi- Expression of PGC-1a partially reverses the toxic cal significance of these events is less well defined.
effects and provides neuroprotection in the HD mutant PGC-1 coactivators in the control of energy metabolism mouse ]. In the peripheral nervous system, PGC-1a has clinical use. For example, coactivators have kinetic benefits been shown to regulate gene expression at the neuromuscu- in controlling biological programs in that they coordinate lar junction and influences expression of acetylcholine different steps in biological programs through the inte- receptors in muscle fibers In addition, elevated gration of the activity of various transcription factors. As PGC-1a levels protect neural cells in culture from cell such, significant biological effects can be achieved by death caused by oxidative-stressor through its induction of quantitatively modulating coactivator function. The diver- sity of post-translational modifications of PGC-1 poten- Energy metabolism in cancer cells differs fundamentally tially allows targeting specific protein – protein interaction from that in its normal counterparts. In general, cancer interface. As discussed above, tissue-specific modulation of cells have high glycolytic activity and prefer glucose as a PGC-1 function is essential for metabolic modulation fuel source, a phenomenon known as the Walburg effect.
without causing deleterious side effects.
The switch from OXPHOS to glycolysis occurs even in thepresence of sufficient oxygen. This aerobic glycolysis has been postulated to enhance cancer cell proliferationand survival. Interestingly, reduced expression of PGC-1a Owing to space limitations, we apologize to those whose has been observed in human breast cancer colon publications related to the discussed issues could not cancer [], liver cancer and ovarian cancer [].
Adenoviral-mediated overexpression of PGC-1a inducesE-cadherin expression while decreasing motility of humanhepatoma HepG2 cells Such manipulation also causes cell apoptosis in human ovarian cancer cells through aPPARg-dependent pathway These findings suggest This work was supported by the grants from the National that PGC-1a is a potentially important regulator of cancer Natural Science Foundation of China (30870928), the cell metabolism and contributes to altered metabolic Research Fund for the Doctoral Program of Higher function in cancer cells. A causal relationship between Education of China (20103207110007), the Fok Ying PGC-1a and cancer development, however, remains to be Tong Education Foundation (121022), the Major Program (09KJA180004) (to C.L.), and the NIH grant (DK077086) The PGC-1 family of transcriptional coactivators has emerged as a regulatory hub within the transcriptional net-works that maintain metabolic homeostasis. The dynamic 1 Puigserver P, Wu Z, Park CW, Graves R, Wright M and Spiegelman BM.
regulation of PGC-1 expression and/or post-translational A cold-inducible coactivator of nuclear receptors linked to adaptive ther- modification in response to nutritional and hormonal mogenesis. Cell 1998, 92: 829 – 839.
signals provides a highly versatile regulatory platform for 2 Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O’Malley B and metabolic control. A major challenge is to map out tissue- Spiegelman BM. Activation of PPARg coactivator-1 through transcription specific activities of PGC-1a and PGC-1b as well as the factor docking. Science 1999, 286: 1368 – 1371.
transcriptional partners that mediate PGC-1 actions. Of 3 Wallberg AE, Yamamura S, Malik S, Spiegelman BM and Roeder RG.
Coordination of p300-mediated chromatin remodeling and TRAP/mediator note, recent genome-wide coactivation analyses provide a function through coactivator PGC-1a. Mol Cell 2003, 12: 1137 – 1149.
global view of potential PGC-1a interacting proteins in 4 Li S, Liu C, Li N, Hao T, Han T, Hill DE and Vidal M, et al.
humans. While the biological function of nuclear receptor Genome-wide coactivation analysis of PGC-1a identifies BAF60a as a targets of PGC-1 is better understood, very little is known regulator of hepatic lipid metabolism. Cell Metab 2008, 8:105 – 117.
about a large number of zinc-finger proteins that associate 5 Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan M and Spiegelman BM. Direct coupling of transcription and mRNA processing through the with PGC-1a. The identification of PGC-1a splicing iso- thermogenic coactivator PGC-1. Mol Cell 2000, 6: 307 – 316.
forms also adds additional complexity Dysregulation 6 Borgius LJ, Steffensen KR, Gustafsson JA and Treuter E. Glucocorticoid of PGC-1 expression has been observed in a wide variety signaling is perturbed by the atypical orphan receptor and core pressor of pathological conditions. As such, proper modulation of SHP. J Biol Chem 2002, 277: 49761 – 49766.
PGC-1a expression/activity has great potential in the 7 Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB and prevention and treatment of diseases associated with Spiegelman BM. PGC-1b in the regulation of hepatic glucose and energy metabolism. J Biol Chem 2003, 278: 30843 – 30848.
impaired mitochondrial function and oxidative metabolism.
8 Andersson U and Scarpulla RC. Pgc-1-related coactivator, a novel, Although targeting a coactivator could be challenging, serum-inducible coactivator of nuclear respiratory factor 1-dependent tran- certain features of coactivator action can be exploited for scription in mammalian cells. Mol Cell Biol 2001, 21: 3738 – 3749.
PGC-1 coactivators in the control of energy metabolism 9 Tiefenbo¨ck SK, Baltzer C, Egli NA and Frei C. The Drosophila PGC-1 27 Uldry M, Yang W, St-Pierre J, Lin J, Seale P and Spiegelman BM.
homologue Spargel coordinates mitochondrial activity to insulin signaling.
Complementary action of the PGC-1 coactivators in mitochondrial biogen- esis and brown fat differentiation. Cell Metab 2006, 3: 333 – 341.
10 Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V and 28 Lelliott CJ, Medina-Gomez G, Petrovic N, Kis A, Feldmann HM, Bjursell Troy A, et al. Mechanisms controlling mitochondrial biogenesis and res- M and Parker N, et al. Ablation of PGC-1b results in defective mitochon- piration through the thermogenic coactivator PGC-1. Cell 1999, 98: drial activity, thermogenesis, hepatic function, and cardiac performance.
11 Esterbauer H, Oberkofler H, Krempler F and Patsch W. Human peroxi- 29 Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O and Michael LF, et al.
some proliferator activated receptor g coactivator 1 (PPARGC1) gene: Transcriptional coactivator PGC-1a drives the formation of slow-twitch cDNA sequence, genomic organization, chromosomal localization, and muscle fibres. Nature 2002, 418: 797 – 801.
tissue expression. Genomics 1999, 62: 98 – 102.
30 Miura S, Tomitsuka E, Kamei Y, Yamazaki T, Kai Y, Tamura M and Kita 12 Knutti D, Kaul A and Kralli A. A tissue-specific coactivator of steroid K, et al. Overexpression of PGC-1a leads to muscle atrophy with receptors, identified in a functional genetic screen. Mol Cell Biol 2000, depletion of ATP. Am J Pathol 2006, 169: 1129 – 1139.
31 Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y and Chin 13 Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S and S, et al. The transcriptional coactivator PGC-1b drives the formation of Yang W, et al. Erra and Gabpa/b specify PGC-1a-dependent oxidative oxidative type IIX fibers in skeletal muscle. Cell Metab 2007, 5: phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 2004, 101: 6570 – 6575.
32 Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J and Adelmant 14 Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M and G, et al. Control of hepatic gluconeogenesis through the transcriptional Oakeley EJ, et al. The estrogen-related receptor a (ERRa) functions in coactivator PGC-1. Nature 2001, 413: 131 – 138.
PPARg coactivator 1a (PGC-1a)-induced mitochondrial biogenesis. Proc 33 Li S, Arning E, Liu C, Vitvitsky V, Hernandez C, Banerjee R and Natl Acad Sci USA 2004, 101: 6472 – 6477.
Bottiglieri T, et al. Regulation of homocysteine homeostasis through the 15 Scarpulla RC. Nuclear activators and coactivators in mammalian mito- transcriptional coactivator PGC-1a. Am J Physiol Endocrinol Metab 2009, chondrial biogenesis. Biochim Biophys Acta 2002, 1576: 1 – 14.
16 Scarpulla RC. Transcriptional activators and coactivators in the nuclear 34 Liu C, Li S, Liu T, Borjigin J and Lin JD. Transcriptional coactivator control of mitochondrial function in mammalian cells. Gene 2002, 286: PGC-1a integrates the mammalian clock and energy metabolism. Nature 17 Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski 35 Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S and Yang W, et al.
M and Barsh GS, et al. Mitochondrial transcription factor A is necessary Hyperlipidemic effects of dietary saturated fats mediated through PGC-1b for mtDNA maintenance and embryogenesis in mice. Nat Genet 1998, 18: coactivation of SREBP. Cell 2005, 120: 261 – 273.
36 Hernandez C, Molusky M, Li Y, Li S and Lin JD. Regulation of hepatic 18 Lin J, Handschin C and Spiegelman BM. Metabolic control through ApoC3 expression by PGC-1b mediates hypolipidemic effect of nicotinic the PGC-1 family of transcription coactivators. Cell Metab 2005, 1: acid. Cell Metab 2010, 12: 411 – 419.
37 Yoon JC, Xu G, Deeney JT, Yang SN, Rhee J, Puigserver P and Levens 19 Liang H and Ward WF. PGC-1a: a key regulator of energy metabolism.
AR, et al. Suppression of b cell energy metabolism and insulin release by Adv Physiol Educ 2006, 30: 145 – 151.
PGC-1a. Dev Cell 2003, 5: 73 – 83.
20 Soyal S, Krempler F, Oberkofler H and Patsch W. PGC-1a: a potent tran- 38 Oberkofler H, Hafner M, Felder T, Krempler F and Patsch W.
scriptional cofactor involved in the pathogenesis of type 2 diabetes.
Diabetologia 2006, 49: 1477 – 1488.
(PPAR) g coactivator-1b is involved in the regulation of glucose-stimulated 21 Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski insulin secretion in INS-1E cells. J Mol Med 2009, 87: 299 – 306.
ER and Gilbert ML, et al. Thermoregulatory and metabolic defects in 39 Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY and Huntington’s disease transgenic mice implicate PGC-1a in Huntington’s Mootha VK, et al. Defects in adaptive energy metabolism with disease neurodegeneration. Cell Metab 2006, 4: 349 – 362.
CNS-linked hyperactivity in PGC-1a null mice. Cell 2004, 119: 121 – 135.
22 St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Ja¨ger S and 40 Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S Handschin C, et al. Suppression of reactive oxygen species and neurode- and Courtois M, et al. PGC-1a deficiency causes multisystem energy generation by the PGC-1 transcriptional coactivators. Cell 2006, 127: metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 2005, 3: e101.
23 Cowell RM, Blake KR and Russell JW. Localization of the transcriptional 41 Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ and coactivator PGC-1a to GABAergic neurons during maturation of the rat Neubauer N, et al. Abnormal glucose homeostasis in skeletal muscle- brain. J Comp Neurol 2007, 502: 1 – 18.
specific PGC-1a knockout mice reveals skeletal muscle-pancreatic beta 24 Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM and Kelly cell crosstalk. J Clin Invest 2007, 117: 3463 – 3474.
42 Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE promotes cardiac mitochondrial biogenesis. J Clin Invest 2000, 106: and Medeiros DM, et al. Cardiac-specific induction of the transcriptional coactivator PGC-1a promotes mitochondrial biogenesis and reversible car- 25 Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP and diomyopathy in a developmental stage-dependent manner. Circ Res 2004, Medeiros DM, et al. Transcriptional coactivators PGC-1a and PGC-1b control overlapping programs required for perinatal maturation of the heart.
43 Vianna CR, Huntgeburth M, Coppari R, Choi CS, Lin J, Krauss S and Barbatelli G, et al. Hypomorphic mutation of PGC-1b causes mitochon- 26 Sonoda J, Mehl IR, Chong LW, Nofsinger RR and Evans RM. PGC-1b drial dysfunction and liver insulin resistance. Cell Metab 2006, 4: controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 2007, 104: 44 Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N and Krainc D.
Transcriptional repression of PGC-1a by mutant huntingtin leads to PGC-1 coactivators in the control of energy metabolism mitochondrial dysfunction and neurodegeneration. Cell 2006, 127: signaling to Pdx1 regulation of pancreatic b cell growth. J Clin Invest 45 Huss JM and Kelly DP. Mitochondrial energy metabolism in heart failure: 63 Ling C, Del Guerra S, Lupi R, Ro¨nn T, Granhall C, Luthman H and a question of balance. J Clin Invest 2005, 115: 547 – 555.
Masiello P, et al. Epigenetic regulation of PPARGC1A in human type 2 46 Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O and Ahmad F, diabetic islets and effect on insulin secretion. Diabetologia 2008, 51: et al. Transcriptional coactivator PGC-1a controls the energy state and contractile function of cardiac muscle. Cell Metab 2005, 1: 259 – 271.
64 Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A and Puigserver P.
47 Lin J, Puigserver P, Donovan J, Tarr P and Spiegelman BM. Peroxisome GCN5 acetyltransferase complex controls glucose metabolism through proliferator-activated receptor gamma coactivator 1b (PGC-1b), a novel transcriptional repression of PGC-1a. Cell Metab 2006, 3: 429 – 438.
PGC-1-related transcription coactivator associated with host cell factor. J 65 Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM and Puigserver P.
Nutrient control of glucose homeostasis through a complex of PGC-1a 48 Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M and Kelly and SIRT1. Nature 2005, 434: 113 – 118.
DP, et al. Adaptations of skeletal muscle to exercise: rapid increase in the 66 Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY and Krauss S, transcriptional coactivator PGC-1. FASEB J 2002, 16: 1879 – 1886.
49 Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I and MAP kinase activation of PPARg coactivator-1. Mol Cell 2001, 8: Shimokawa T. cDNA cloning and mRNA analysis of PGC-1 in epitro- chlearis muscle in swimming-exercised rats. Biochem Biophys Res 67 Jager S, Handschin C, St-Pierre J and Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphoryl- 50 Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E and Gustafsson ation of PGC-1a. Proc Natl Acad Sci USA 2007, 104: 12017 – 12022.
T. PGC-1a mRNA expression is influenced by metabolic perturbation in 68 Li X, Monks B, Ge Q and Birnbaum MJ. Akt/PKB regulates hepatic exercising human skeletal muscle. J Appl Physiol 2004, 96: 189 – 194.
metabolism by directly inhibiting PGC-1a transcription coactivator. Nature 51 Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB and Williams RS, et al. Exercise stimulates PGC-1a transcription in skeletal 69 Teyssier C, Ma H, Emter R, Kralli A and Stallcup MR. Activation of muscle through activation of the p38 MAPK pathway. J Biol Chem 2005, nuclear receptor coactivator PGC-1a by arginine methylation. Genes Dev 52 Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby 70 Rytinki MM and Palvimo JJ. SUMOylation attenuates the function of R and Williams RS. Regulation of mitochondrial biogenesis in skeletal PGC-1a. J Biol Chem 2009, 284: 26184 – 26193.
muscle by CaMK. Science 2002, 296: 349 – 352.
71 Canto´ C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC 53 Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ and Shulman GI. AMP kinase is required for mitochondrial biogenesis in skel- modulating NADþ metabolism and SIRT1 activity. Nature 2009, 458: etal muscle in response to chronic energy deprivation. Proc Natl Acad Sci 72 Kelly TJ, Lerin C, Haas W, Gygi SP and Puigserver P. GCN5-mediated 54 Olesen J, Kiilerich K and Pilegaard H. PGC-1a-mediated adaptations in transcriptional control of the metabolic coactivator PGC-1b through lysine skeletal muscle. Pflugers Arch 2010, 460: 153 – 162.
acetylation. J Biol Chem 2009, 284: 19945 – 19952.
55 Mortensen OH, Frandsen L, Schjerling P, Nishimura E and Grunnet N.
73 Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S and PGC-1a and PGC-1b have both similar and distinct effects on myofiber Miyazaki Y, et al. Coordinated reduction of genes of oxidative metabolism switching toward an oxidative phenotype. Am J Physiol Endocrinol Metab in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 2003, 100: 8466 – 8471.
56 Rodrı´guez-Calvo R, Jove´ M, Coll T, Camins A, Sa´nchez RM, Alegret M and 74 Semple RK, Crowley VC, Sewter CP, Laudes M, Christodoulides C, Merlos M, et al. PGC-1b down-regulation is associated with reduced ERRa Considine RV and Vidal-Puig A, et al. Expression of the thermogenic activity and MCAD expression in skeletal muscle of senescence-accelerated nuclear hormone receptor coactivator PGC-1a is reduced in the adipose mice. J Gerontol A Biol Sci Med Sci 2006, 61: 773–780.
tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 2004, 57 Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R and Evans RM, et al. PGC-1 promotes insulin resistance in liver through 75 Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J PPAR-a-dependent induction of TRB-3. Nat Med 2004, 10: 530 – 534.
and Straubhaar J, et al. Mitochondrial remodeling in adipose tissue associ- 58 Wolfrum C and Stoffel M. Coactivation of Foxa2 through PGC-1b pro- ated with obesity and treatment with rosiglitazone. J Clin Invest 2004, motes liver fatty acid oxidation and triglyceride/VLDL secretion. Cell 76 Puigserver P and Spiegelman BM. Peroxisome proliferator-activated 59 Nagai Y, Yonemitsu S, Erion DM, Iwasaki T, Stark R, Weismann D and receptor-g coactivator 1a (PGC-1a): transcriptional coactivator and meta- Dong J, et al. The role of peroxisome proliferator-activated receptor bolic regulator. Endocr Rev 2003, 24: 78 – 90.
gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin 77 Choi CS, Befroy DE, Codella R, Kim S, Reznick RM, Hwang YJ and Liu resistance. Cell Metab 2009, 9: 252 – 264.
ZX, et al. Paradoxical effects of increased expression of PGC-1a on 60 De Souza CT, Gasparetti AL, Pereira-da-Silva M, Arau´jo EP, Carvalheira muscle mitochondrial function and insulin-stimulated muscle glucose JB, Saad MJ and Boschero AC, et al. Peroxisome proliferator-activated metabolism. Proc Natl Acad Sci USA 2008, 105: 19926 – 19931.
receptor gamma coactivator-1-dependent uncoupling protein-2 expression 78 Ek J, Andersen G, Urhammer SA, Gaede PH, Drivsholm T, Borch in pancreatic islets of rats: a novel pathway for neural control of insulin Johnsen K and Hansen T, et al. Mutation analysis of peroxisome secretion. Diabetologia 2003, 46: 1522 – 1531.
proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relation- 61 Zhang P, Liu C, Zhang C, Zhang Y, Shen P, Zhang J and Zhang CY. Free ships of identified amino acid polymorphisms to type II diabetes mellitus.
fatty acids increase PGC-1a expression in isolated rat islets. FEBS Lett Diabetologia 2001, 44: 2220 – 2226.
79 Mistry NF and Cresci S. PPAR transcriptional activator complex poly- 62 Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs WH, III, Wright CV and morphisms and the promise of individualized therapy for heart failure.
White MF, et al. The forkhead transcription factor Foxo1 links insulin Heart Fail Rev 2010, 15: 197 – 207.
PGC-1 coactivators in the control of energy metabolism 80 Zhang Y, Liu C, Zhu L, Jiang X, Chen X, Qi X and Liang X, et al.
86 Feilchenfeldt J, Bru¨ndler MA, Soravia C, To¨tsch M and Meier CA.
PGC-1a inhibits oleic acid induced proliferation and migration of rat vas- Peroxisome proliferator-activated receptors (PPARs) and associated tran- cular smooth muscle cells. PLoS One 2007, 2: e1137.
scription factors in colon cancer: reduced expression of PPARg-coactivator 81 Zhu L, Sun G, Zhang H, Zhang Y, Chen X, Jiang X and Jiang X, et al.
1 (PGC-1). Cancer Lett 2004, 203: 25 – 33.
PGC-1a is a key regulator of glucose-induced proliferation and migration 87 Ba Y, Zhang CN, Zhang Y and Zhang CY. Down-regulation of PGC-1a in vascular smooth muscle cells. PLoS One 2009, 4: e4182.
expression in human hepatocellular carcinoma. Zhonghua Zhong Liu Za 82 Valle I, Alvarez-Barrientos A, Arza E, Lamas S and Monsalve M.
PGC-1a regulates the mitochondrial antioxidant defense system in vascu- 88 Zhang Y, Ba Y, Liu C, Sun G, Ding L, Gao S and Hao J, et al. PGC-1a lar endothelial cells. Cardiovasc Res 2005, 66: 562 – 573.
induces apoptosis in human epithelial ovarian cancer cells through a 83 Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S and Arning L. PGC-1a as PPARg-dependent pathway. Cell Res 2007, 17: 363 – 373.
modifier of onset age in Huntington disease. Mol Neurodegener 2009, 4: 10.
89 Lee HJ, Su Y, Yin PH, Lee HC and Chi CW. PPARg/PGC-1a pathway in 84 Handschin C, Kobayashi YM, Chin S, Seale P, Campbell KP and E-cadherin expression and motility of HepG2 cells. Anticancer Res 2009, Spiegelman BM. PGC-1a regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 2007, 21: 770– 783.
90 Zhang Y, Huypens P, Adamson AW, Chang JS, Henagan TM, Boudreau 85 Watkins G, Douglas-Jones A, Mansel RE and Jiang WG. The localization A and Lenard NR, et al. Alternative mRNA splicing produces a novel bio- and reduction of nuclear staining of PPARg and PGC-1 in human breast logically active short isoform of PGC-1a. J Biol Chem 2009, 284: cancer. Oncol Rep 2004, 12: 483 – 488.
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