Metabolic control through the PGC-1 family of transcription coactivators
2005; Cell Press; Volume: 1; Issue: 6 Linguagem: Inglês
10.1016/j.cmet.2005.05.004
ISSN1932-7420
AutoresJiandie D. Lin, Christoph Handschin, Bruce M. Spiegelman,
Tópico(s)Lipid metabolism and biosynthesis
ResumoMany complex biological programs are controlled at the level of gene transcription by DNA binding transcription factors. Recent studies have revealed a novel mode of regulation by coactivator proteins, best illustrated by the PGC-1 family of coactivators. These factors are highly responsive to a variety of environmental cues, from temperature to nutritional status to physical activity, and they coordinately regulate metabolic pathways and biological processes in a tissue-specific manner. Notably, the PGC-1 coactivators play a critical role in the maintenance of glucose, lipid, and energy homeostasis and are likely involved in the pathogenic conditions such as obesity, diabetes, neurodegeneration, and cardiomyopathy. These actions also raise new opportunities for the development of novel therapeutics. Many complex biological programs are controlled at the level of gene transcription by DNA binding transcription factors. Recent studies have revealed a novel mode of regulation by coactivator proteins, best illustrated by the PGC-1 family of coactivators. These factors are highly responsive to a variety of environmental cues, from temperature to nutritional status to physical activity, and they coordinately regulate metabolic pathways and biological processes in a tissue-specific manner. Notably, the PGC-1 coactivators play a critical role in the maintenance of glucose, lipid, and energy homeostasis and are likely involved in the pathogenic conditions such as obesity, diabetes, neurodegeneration, and cardiomyopathy. These actions also raise new opportunities for the development of novel therapeutics. Transcription factors function through the docking of specific coactivator or corepressor proteins. While transcription factors bind to DNA in a sequence-specific fashion, they generally lack the enzymatic activities necessary to modify chromatin, unwind DNA, and recruit RNA polymerase II. These biochemical activities are the job of coregulators, which usually exist as multiprotein complexes in the nucleus, and can be recruited to transcription factors in response to cellular signals. Until recently, most studies of biological processes controlled at the transcriptional level have focused on changes in the amounts or activities of transcription factors. While this is undoubtedly a major mode of regulation, it has become very clear that transcriptional coactivator proteins can be highly regulated and can, in fact, be the primary targets of hormonal control and signal transduction pathways (Spiegelman and Heinrich, 2004Spiegelman B.M. Heinrich R. Biological control through regulated transcriptional coactivators.Cell. 2004; 119: 157-167Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). Perhaps the best examples of this are the PGC-1 (PPARγ coactivator-1) coactivators. While these proteins were not the first coactivators shown to be highly regulated, their regulation and biological function have been studied in greatest detail. In fact, the PGC-1 family of coactivators has emerged as major players that integrate signaling pathways in the control of cellular and systemic metabolism. The role of the PGC-1 coactivators in the regulation of mitochondrial oxidative metabolism and the maintenance of glucose, lipid, and energy homeostasis will be discussed in this review. The first member of the PGC-1 family was identified as a PPARγ-interacting protein from brown fat and is now termed PGC-1α (Puigserver et al., 1998Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (2857) Google Scholar). PGC-1β is the closest homolog of PGC-1α and shares extensive sequence identity (Kressler et al., 2002Kressler D. Schreiber S.N. Knutti D. Kralli A. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha.J. Biol. Chem. 2002; 277: 13918-13925Crossref PubMed Scopus (185) Google Scholar, Lin et al., 2002aLin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor.J. Biol. Chem. 2002; 277: 1645-1648Crossref PubMed Scopus (422) Google Scholar), clustered in several distinct domains (Figures 1A and 1B ), including an N-terminal activation domain (40%), a central regulatory domain (35%), and a C-terminal RNA binding domain (48%). PGC-related coactivator (PRC) has more limited homology (Andersson and Scarpulla, 2001Andersson U. Scarpulla R.C. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells.Mol. Cell. Biol. 2001; 21: 3738-3749Crossref PubMed Scopus (283) Google Scholar), including the activation domain and RNA binding domain. Sequence analysis reveals that the PGC-1 family of coactivators is conserved in many chordate species, including primates, rodents, ruminants, birds, amphibians, and fishes (Figure 2). These coactivators have similar domain structure and several signature motifs, most notably TPPTTPP and DHDYCQ (Lin et al., 2002aLin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor.J. Biol. Chem. 2002; 277: 1645-1648Crossref PubMed Scopus (422) Google Scholar), that are present in all family members. To date, no clear PGC-1 homolog has been found in lower eukaryotes including worm, fly, and yeast.Figure 2Conservation of the PGC-1 family of coactivators in vertebratesShow full captionAmino acid sequences of the PGC-1 family of coactivators currently available in the GenBank database are aligned using the Clustal program. The relative distance represents the degree of sequence identity among different members. Note that the absence of certain members in some species is likely due to the lack of full-length cDNA sequences in available databases.View Large Image Figure ViewerDownload (PPT) Amino acid sequences of the PGC-1 family of coactivators currently available in the GenBank database are aligned using the Clustal program. The relative distance represents the degree of sequence identity among different members. Note that the absence of certain members in some species is likely due to the lack of full-length cDNA sequences in available databases. The PGC-1 coactivators have powerful transcriptional activity when linked to a heterologous DNA binding domain (Knutti et al., 2000Knutti D. Kaul A. Kralli A. A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen.Mol. Cell. Biol. 2000; 20: 2411-2422Crossref PubMed Scopus (230) Google Scholar, Lin et al., 2002aLin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor.J. Biol. Chem. 2002; 277: 1645-1648Crossref PubMed Scopus (422) Google Scholar, Puigserver et al., 1998Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (2857) Google Scholar), or when they dock on a transcription factor. While they have not been found to encode any histone acetyltransferase (HAT) activities in their primary sequence, they bind several powerful HAT-containing proteins at their N-terminal regions, including CBP, p300, and SRC-1 (Puigserver et al., 1999Puigserver P. Adelmant G. Wu Z. Fan M. Xu J. O’Malley B. Spiegelman B.M. Activation of PPARgamma coactivator-1 through transcription factor docking.Science. 1999; 286: 1368-1371Crossref PubMed Scopus (472) Google Scholar). These proteins acetylate histones and remodel chromatin structure to allow access of additional factors for gene activation (Figure 1B). In addition, several proteins encompassing the mediator complex (also known as the TRAP/DRIP complex) dock in the C-terminal region of PGC-1α (Wallberg et al., 2003Wallberg A.E. Yamamura S. Malik S. Spiegelman B.M. Roeder R.G. Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha.Mol. Cell. 2003; 12: 1137-1149Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). This region also harbors a Ser/Arg-rich domain and an RNA binding domain and has been shown to couple pre-mRNA splicing with transcription (Monsalve et al., 2000Monsalve M. Wu Z. Adelmant G. Puigserver P. Fan M. Spiegelman B.M. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1.Mol. Cell. 2000; 6: 307-316Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). The PGC-1α transcriptional activator complex is able to displace repressor proteins, such as histone deacetylase and small heterodimer partner (SHP), on its target promoters, leading to augmented gene transcription (Borgius et al., 2002Borgius L.J. Steffensen K.R. Gustafsson J.A. Treuter E. Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP.J. Biol. Chem. 2002; 277: 49761-49766Crossref PubMed Scopus (103) Google Scholar, Guan et al., 2005Guan H.P. Ishizuka T. Chui P.C. Lehrke M. Lazar M.A. Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes.Genes Dev. 2005; 19: 453-461Crossref PubMed Scopus (239) Google Scholar). A critical aspect of the PGC-1 coactivators is that they are highly versatile and have the ability to interact with many different transcription factors (Table 1); in doing so, they activate distinct biological programs in different tissues. PGC-1α, for example, can bind to and coactivate most members of the nuclear receptor family—often in a ligand-dependent manner (such as the ER) but sometimes without the addition of a ligand, such as with PPARγ (Puigserver and Spiegelman, 2003Puigserver P. Spiegelman B.M. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator.Endocr. Rev. 2003; 24: 78-90Crossref PubMed Scopus (1506) Google Scholar). PGC-1 also targets transcription factors outside of the nuclear receptor superfamily, such as SREBP (Lin et al., 2005Lin J. Yang R. Tarr P.T. Wu P.H. Handschin C. Li S. Yang W. Pei L. Uldry M. Tontonoz P. et al.Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP.Cell. 2005; 120: 261-273Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar), FOXO1 (Puigserver et al., 2003Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1090) Google Scholar), and Sox9 (Kawakami et al., 2005Kawakami Y. Tsuda M. Takahashi S. Taniguchi N. Rodriguez Esteban C. Zemmyo M. Furumatsu T. Lotz M. Izpisua Belmonte J.C. Asahara H. Transcriptional coactivator PGC-1{alpha} regulates chondrogenesis via association with Sox9.Proc. Natl. Acad. Sci. USA. 2005; 102: 2414-2419Crossref PubMed Scopus (122) Google Scholar). Table 1 summarizes transcription factor targets of PGC-1α and β and their respective roles in mediating certain aspects of PGC-1 function. Many of these proteins dock in a central region between the N-terminal activation domain and the C-terminal SR and RNA binding domains. In addition, PGC-1α has three functional LXXLL motifs that are used for the binding of many nuclear receptors (Knutti et al., 2000Knutti D. Kaul A. Kralli A. A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen.Mol. Cell. Biol. 2000; 20: 2411-2422Crossref PubMed Scopus (230) Google Scholar, Puigserver et al., 1998Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (2857) Google Scholar). The fact that PGC-1α and β contain distinct binding sites for different transcription factors raises the interesting possibility that alleles can be made experimentally, or may exist naturally, that can carry out only a subset of functions that the full-length proteins can stimulate. In fact, both PGC-1α and β mRNAs are alternatively spliced to generate multiple isoforms, though the functional significance of this remains unknown (Baar et al., 2002Baar K. Wende A.R. Jones T.E. Marison M. Nolte L.A. Chen M. Kelly D.P. Holloszy J.O. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1.FASEB J. 2002; 16: 1879-1886Crossref PubMed Scopus (729) Google Scholar, Kamei et al., 2003Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.Proc. Natl. Acad. Sci. USA. 2003; 100: 12378-12383Crossref PubMed Scopus (295) Google Scholar, Meirhaeghe et al., 2003Meirhaeghe A. Crowley V. Lenaghan C. Lelliott C. Green K. Stewart A. Hart K. Schinner S. Sethi J.K. Yeo G. et al.Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo.Biochem. J. 2003; 373: 155-165Crossref PubMed Scopus (165) Google Scholar).Table 1Transcription factor targets of the PGC-1 coactivatorsTranscription factorPGC-1αPGC-1βFunctionReferencesNRF-1++mitochondrial genesWu et al., 1999Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (2904) Google ScholarNRF-2+NDmitochondrial genesMootha et al., 2003Mootha V.K. Lindgren C.M. Eriksson K.F. Subramanian A. Sihag S. Lehar J. Puigserver P. Carlsson E. Ridderstrale M. Laurila E. et al.PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.Nat. Genet. 2003; 34: 267-273Crossref PubMed Scopus (5043) Google ScholarPPARα++fatty-acid oxidationVega et al., 2000Vega R.B. Huss J.M. Kelly D.P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.Mol. Cell. Biol. 2000; 20: 1868-1876Crossref PubMed Scopus (863) Google ScholarPPARβ/δ+NDfatty-acid oxidationWang et al., 2003Wang Y.X. Lee C.H. Tiep S. Yu R.T. Ham J. Kang H. Evans R.M. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity.Cell. 2003; 113: 159-170Abstract Full Text Full Text PDF PubMed Scopus (1087) Google ScholarPPARγ++UCP1/GyK inductionGuan et al., 2005Guan H.P. Ishizuka T. Chui P.C. Lehrke M. Lazar M.A. Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes.Genes Dev. 2005; 19: 453-461Crossref PubMed Scopus (239) Google Scholar; Puigserver et al., 1998Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (2857) Google ScholarERRα,β,γ++mitochondrial genesHuss et al., 2002Huss J.M. Kopp R.P. Kelly D.P. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha.J. Biol. Chem. 2002; 277: 40265-40274Crossref PubMed Scopus (376) Google Scholar; Huss et al., 2004Huss J.M. Torra I.P. Staels B. Giguere V. Kelly D.P. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle.Mol. Cell. Biol. 2004; 24: 9079-9091Crossref PubMed Scopus (365) Google Scholar; Kamei et al., 2003Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.Proc. Natl. Acad. Sci. USA. 2003; 100: 12378-12383Crossref PubMed Scopus (295) Google Scholar; Mootha et al., 2004Mootha V.K. Handschin C. Arlow D. Xie X. St Pierre J. Sihag S. Yang W. Altshuler D. Puigserver P. Patterson N. et al.Err{alpha} and Gabpa/b specify PGC-1{alpha}-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.Proc. Natl. Acad. Sci. USA. 2004; 101: 6570-6575Crossref PubMed Scopus (533) Google Scholar; Schreiber et al., 2004Schreiber S.N. Emter R. Hock M.B. Knutti D. Cardenas J. Podvinec M. Oakeley E.J. Kralli A. The estrogen-related receptor {alpha} (ERR{alpha}) functions in PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha})-induced mitochondrial biogenesis.Proc. Natl. Acad. Sci. USA. 2004; 101: 6472-6477Crossref PubMed Scopus (467) Google ScholarTRβ++cpt-1 inductionWu et al., 2002Wu H. Kanatous S.B. Thurmond F.A. Gallardo T. Isotani E. Bassel-Duby R. Williams R.S. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK.Science. 2002; 296: 349-352Crossref PubMed Scopus (507) Google Scholar; Zhang et al., 2004bZhang Y. Ma K. Song S. Elam M.B. Cook G.A. Park E.A. 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Knutti D. Kralli A. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha.J. Biol. Chem. 2002; 277: 13918-13925Crossref PubMed Scopus (185) Google ScholarPXR+NDunknownBhalla et al., 2004Bhalla S. Ozalp C. Fang S. Xiang L. Kemper J.K. Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism.J. Biol. Chem. 2004; 279: 45139-45147Crossref PubMed Scopus (171) Google ScholarSox9+NDchondrogenesisKawakami et al., 2005Kawakami Y. Tsuda M. Takahashi S. Taniguchi N. Rodriguez Esteban C. Zemmyo M. Furumatsu T. Lotz M. Izpisua Belmonte J.C. Asahara H. Transcriptional coactivator PGC-1{alpha} regulates chondrogenesis via association with Sox9.Proc. Natl. Acad. Sci. USA. 2005; 102: 2414-2419Crossref PubMed Scopus (122) Google ScholarMEF2+NDslow fiber genesLin et al., 2002bLin J. Wu H. Tarr P.T. Zhang C.Y. Wu Z. Boss O. Michael L.F. Puigserver P. Isotani E. Olson E.N. et al.Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.Nature. 2002; 418: 797-801Crossref PubMed Scopus (1908) Google Scholar; Michael et al., 2001Michael L.F. Wu Z. Cheatham R.B. Puigserver P. Adelmant G. Lehman J.J. Kelly D.P. Spiegelman B.M. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1.Proc. Natl. Acad. Sci. USA. 2001; 98: 3820-3825Crossref PubMed Scopus (504) Google ScholarFOXO1+−gluconeogenesisPuigserver et al., 2003Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1090) Google ScholarHNF4α+±gluconeogenesisLin et al., 2002aLin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor.J. Biol. Chem. 2002; 277: 1645-1648Crossref PubMed Scopus (422) Google Scholar; Yoon et al., 2001Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. et al.Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.Nature. 2001; 413: 131-138Crossref PubMed Scopus (1436) Google ScholarSREBP1a, 1c, 2−+lipogenesis/ lipoprotein secretionLin et al., 2005Lin J. Yang R. Tarr P.T. Wu P.H. Handschin C. Li S. Yang W. Pei L. Uldry M. Tontonoz P. et al.Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP.Cell. 2005; 120: 261-273Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar Open table in a new tab Of the transcription factors that PGC-1α and β coactivate, one subset draws special attention; this includes NRF-1 and NRF-2 (Wu et al., 1999Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar) and the nuclear hormone receptors, such as PPARα (Vega et al., 2000Vega R.B. Huss J.M. Kelly D.P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.Mol. Cell. Biol. 2000; 20: 1868-1876Crossref PubMed Scopus (863) Google Scholar), PPARδ (Wang et al., 2003Wang Y.X. Lee C.H. Tiep S. Yu R.T. Ham J. Kang H. Evans R.M. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity.Cell. 2003; 113: 159-170Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar), ERRα (Huss et al., 2002Huss J.M. Kopp R.P. Kelly D.P. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha.J. Biol. Chem. 2002; 277: 40265-40274Crossref PubMed Scopus (376) Google Scholar, Huss et al., 2004Huss J.M. Torra I.P. Staels B. Giguere V. Kelly D.P. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle.Mol. Cell. Biol. 2004; 24: 9079-9091Crossref PubMed Scopus (365) Google Scholar, Kamei et al., 2003Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.Proc. Natl. Acad. Sci. USA. 2003; 100: 12378-12383Crossref PubMed Scopus (295) Google Scholar, Mootha et al., 2004Mootha V.K. Handschin C. Arlow D. Xie X. St Pierre J. Sihag S. Yang W. Altshuler D. Puigserver P. Patterson N. et al.Err{alpha} and Gabpa/b specify PGC-1{alpha}-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.Proc. Natl. Acad. Sci. USA. 2004; 101: 6570-6575Crossref PubMed Scopus (533) Google Scholar, Schreiber et al., 2004Schreiber S.N. Emter R. Hock M.B. Knutti D. Cardenas J. Podvinec M. Oakeley E.J. Kralli A. The estrogen-related receptor {alpha} (ERR{alpha}) functions in PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha})-induced mitochondrial biogenesis.Proc. Natl. Acad. Sci. USA. 2004; 101: 6472-6477Crossref PubMed Scopus (467) Google Scholar), and TR (Zhang et al., 2004bZhang Y. Ma K. Song S. Elam M.B. Cook G.A. Park E.A. Peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-I alpha).J. Biol. Chem. 2004; 279: 53963-53971Crossref PubMed Scopus (66) Google Scholar) (Table 1). All of these transcription factors directly regulate the expression of certain nuclear-encoded mitochondrial genes and were discussed in greater detail in two recent reviews (Kelly and Scarpulla, 2004Kelly D.P. Scarpulla R.C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function.Genes Dev. 2004; 18: 357-368Crossref PubMed Scopus (901) Google Scholar, Puigserver and Spiegelman, 2003Puigserver P. Spiegelman B.M. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator.Endocr. Rev. 2003; 24: 78-90Crossref PubMed Scopus (1506) Google Scholar). NRF-1 and 2 are themselves targets of PGC-1α (Wu et al., 1999Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar) and are able to stimulate the expression of mitochondrial transcription factor A (Tfam), a mitochondrial matrix protein essential for the replication and transcription of mitochondrial DNA (Clayton, 1991Clayton D.A. Replication and transcription of vertebrate mitochondrial DNA.Annu. Rev. Cell Biol. 1991; 7: 453-478Crossref PubMed Scopus (511) Google Scholar, Parisi and Clayton, 1991Parisi M.A. Clayton D.A. Similarity of human mitochondrial transcription factor 1 to high mobility group proteins.Science. 1991; 252: 965-969Crossref PubMed Scopus (426) Google Scholar, Virbasius and Scarpulla, 1994Virbasius J.V. Scarpulla R.C. 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Chem. 2003; 278: 26597-26603Crossref PubMed Scopus (455) Google Scholar, Wu et al., 1999Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar). These two coactivators stimulate the biogenesis of mitochondria with different metabolic characteristics, reflecting the fact that they regulate the expression of overlapping but distinct sets of mitochondrial genes. For example, respiration stimulated by PGC-1β is more highly coupled than that induced by PGC-1α, when they are expressed in differentiated C2C12 myotubes (St-Pierre et al., 2003St-Pierre J. Lin J. Krauss S. Tarr P.T. Yang R. Newgard C.B. Spiegelman B.M. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells.J. Biol. Chem. 2003; 278: 26597-26603Crossref PubMed Scopus (455) Google Scholar). Thus, modulating the relative activity of PGC-1α and β within the cell may lead to fine-tuning of mitochondrial function in response to specific m
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