Reversible Acetylation of PGC-1: Connecting Energy Sensors and Effectors to Guarantee Metabolic ﬂexibility

Oncogene (2010) 29, 4617–4624 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility EH Jeninga, K Schoonjans and J Auwerx Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), Laboratory of Integrative and Systems Physiology, Lausanne, Switzerland Organisms adapt their metabolism to meet ever changing of diseases, such as metabolic disorders and cancer. environmental conditions. This metabolic adaptation Metabolic homeostasis is to a large extent controlled by involves at a cellular level the fine tuning of mitochondrial transcriptional regulatory mechanisms, which involve function, which is mainly under the control of the the coordinated action of transcription factors, cofac- transcriptional co-activator proliferator-activated recep- tors and the transcription initiation machinery regulat- tor c co-activator (PGC)-1a. Changes in PGC-1a activity ing the expression of genes involved in mitochondrial coordinate a transcriptional response, which boosts biogenesis and function (Kelly and Scarpulla, 2004). mitochondrial activity in times of energy needs and The transcriptional co-activator proliferator-activated attenuates it when energy demands are low. Reversible receptor g co-activator 1a (PGC-1a) is the master acetylation has emerged as a key way to alter PGC-1a regulator of mitochondrial biogenesis and function activity. Although it is well established that PGC-1a is (Puigserver et al., 1998; Wu et al., 1999). PGC-1a deacetylated and activated by Sirt1 and acetylated and expression and activity is regulated at multiple levels and inhibited by GCN5, less is known regarding how these by diverse signaling events. Within the whole array of enzymes themselves are regulated. Recently, it became regulatory events that converge on PGC-1a, reversible clear that the energy sensor, AMP-activated kinase acetylation only recently emerged as the key modifier (AMPK) translates the effects of energy stress into of PGC-1a activity. The acetylation state of PGC-1a altered Sirt1 activity by regulating the intracellular level is regulated by the deacetylase Sirt1 and the acetyl- of its co-substrate nicotinamide adenine dinucleotide transferase GCN5. Interestingly, the activity of both (NAD) þ . Conversely, the enzyme ATP citrate lyase the Sirt1 and GCN5 proteins are modulated by the (ACL), relates energy balance to GCN5, through energy status of the cell. This review will focus on the the control of the nuclear production of acetyl-CoA, the direct regulators of the PGC1-a acetylation state, Sirt1 substrate for GCN5’s acetyltransferase activity. We and GCN5, as well as on the pathways that provide the review here how these metabolic signaling pathways, substrates for the deacetylation and acetylation reaction, affecting GCN5 and Sirt1 activity, allow the reversible respectively. acetylation–deacetylation of PGC-1a and the adaptation of mitochondrial energy homeostasis to energy levels. Oncogene (2010) 29, 4617–4624; doi:10.1038/onc.2010.206; published online 7 June 2010 PGC-1a, an important regulator of energy homeostasis Keywords: AMPK; ATP citrate lyase; GCN5; mito- As exemplified by its name, peroxisome proliferator- chondria; PGC-1a; SIRT1 activated receptor g co-activator 1a (PGC-1a) was originally identified as a transcriptional co-activator of the nuclear receptor PPARg (Puigserver et al., 1998). It is now established that PGC-1a interacts with several Introduction other transcription factors, including PPARa, glucocor- ticoid receptor, hepatic nuclear factor 4a, estrogen When energy levels are limiting, such as during fasting receptor related a and FOXO1 (Vega et al., 2000; Yoon and exercise, peripheral tissues switch to use fatty acids et al., 2001; Puigserver et al., 2003). By binding and as fuel for mitochondrial oxidation to preserve blood modulating the activity of these different transcription glucose for cells that strictly rely on glucose as their factors, PGC-1a fine tunes the expression of a number main energy source, such as neurons and red blood cells. of genes involved in diverse metabolic pathways, such as This metabolic flexibility is critically important, as fatty acid oxidation, gluconeogenesis, glycolysis and inappropriate adaptation is often the basis for the onset fatty acid synthesis. In brown adipose tissue, PGC-1a controls adaptive thermogenesis by increasing mito- Correspondence: Dr J Auwerx, Ecole Polytechnique Federale de chondrial fatty acid oxidation and heat production Lausanne, EPFL-SV-IBI1—LISP—NCEM1, Baˆtiment AI (AI 1.145), through the expression of uncoupling protein 1 after Station 15, CH-1015 Lausanne, Switzerland. E-mail: admin.auwerx@epfl.ch cold exposure (Puigserver et al., 1998). In liver, fasting Received 8 March 2010; revised 22 April 2010; accepted 25 April 2010; increases PGC-1a expression thereby promoting gluco- published online 7 June 2010 neogenesis and repressing glycolysis, which results in an Cofactors as energy sensors EH Jeninga et al 4618 increased hepatic glucose output (Yoon et al., 2001). Canto et al., 2009). These findings indicate that PGC-1a is Fasting and exercise induces PGC-1a-mediated mito- activated by Sirt1-mediated deacetylation in times of chondrial biogenesis and fatty acid oxidation in the energy demand, such as fasting and physical activity. muscle (Wu et al., 1999; Gerhart-Hines et al., 2007; As Sirt1 requires the coenzyme nicotinamide adenine Canto et al., 2009). The expression and activity of PGC- dinucleotide (NAD þ ) as a co-substrate for its function 1a is regulated by both cell-autonomous factors, such as (Imai et al., 2000), this suggests that NAD þ , NADH or AMP-activated kinase (AMPK) and mTOR (Herzig the NAD þ /NADH ratio modulates its activity, thereby et al., 2001; Yoon et al., 2001; Canto et al., 2009), as well linking Sirt1 activity to the energy status of the cell. as by systemic factors of hormonal origin, such as Intracellular NAD þ levels are regulated by the balance insulin, glucagon and glucocorticoids and centrally between NAD þ synthesis, either de novo or by recycling regulated neural outputs (Puigserver et al., 2003). In through the NAD þ salvage pathway, and NAD þ addition to the regulation of its expression level, PGC- consumption by NAD þ -dependent enzymes (reviewed 1a activity is controlled by a variety of posttranslational in Houtkooper et al. (2010)). In addition, AMPK can modifications, including phosphorylation (Puigserver modulate this balance through altering metabolic et al., 2003; Jager et al., 2007; Li et al., 2007), ubiquiti- pathways, as recently shown (Fulco et al., 2008; Canto nation (Olson et al., 2008) and acetylation (Rodgers et al., 2009, 2010). et al., 2005; Lerin et al., 2006). Of all these posttranslational events reversible acetylation has emerged as a key modifier of PGC-1a activity. Tandem mass spectro- NAD þ synthesis and NAD þ consumption metry analysis of PGC-1a identified 13 acetylation sites (Rodgers et al., 2005) and so far only two proteins have Although NAD þ can be synthesized de novo from the been unequivocally shown to be involved in the amino acid tryptophan derived from the diet, it is reversible acetylation of PGC-1a, the deacetylase Sirt1 assumed that the main source of NAD þ is produced (Nemoto et al., 2005; Rodgers et al., 2005) and the through the so-called NAD þ salvage pathways. This acetyltransferase GCN5 (Lerin et al., 2006). requires the dietary uptake of NAD þ precursors, such as the niacin-derived nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR), which in Deacetylation and activation of PGC-1a by Sirt1 mammals are converted into NAD þ through the salvage pathway (see Figure 1). In this pathway, NAM is Up to date, the only protein identified to be able to thought to be the most important contributor to NAD þ deacetylate PGC-1a is Sirt1 (Nemoto et al., 2005; synthesis. The conversion of NAM to NAD þ is different Gerhart-Hines et al., 2007; Rodgers and Puigserver, between yeast and mammals. In yeast, NAM, the end 2007). Sirt1 belongs to a family of class III histone/ product of reactions catalyzed by NAD þ -consuming protein deacetylase proteins, compromised of seven enzymes, is converted to NA by the enzyme pyrazina- members in mammals (that is, Sirt1–Sirt7), with midase/nicotinamidase 1 (Pnc1), followed by the different cellular localization. Sirt1 is the mammalian conversion to NAM mononucleotide. In contrast, in homolog of the Silent information regulator 2 (Sir2), mammals NAM is directly converted to NAM mono- which was initially identified as a trans-acting factor nucleotide by one of the NAM phosphoribosyltransfer- involved in repression of the silent mating-type loci in ase (Nampt) enzymes. In both yeast and mammals, yeast (Shore et al., 1984). In addition to silencing, Sir2 NAM mononucleotide is subsequently converted to activity is linked to lifespan extension in yeast (Kae- NAD þ . Interestingly, mutating either Sir2 or Pnc1 berlein et al., 1999), worms (Tissenbaum and Guarente, abolishes lifespan expansion after caloric restriction in 2001) and flies (Rogina and Helfand, 2004), indicating yeast (Lin et al., 2000). In addition, in skeletal muscle that Sir2 has conserved its function throughout evolu- the level of Nampt increases upon exercise (Costford tion. In contrast to mammals, in yeast only five et al., 2009; Canto et al., 2010) as well as in muscle of homologs exits; ySir2 and Hst1–4 (homologous to mice on fasting (Canto

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