Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility

Abstract

Organisms adapt their metabolism to meet ever changing environmental conditions. This metabolic adaptation involves at a cellular level the fine tuning of mitochondrial function, which is mainly under the control of the transcriptional co-activator proliferator-activated receptor gamma co-activator (PGC)-1alpha. Changes in PGC-1alpha activity coordinate a transcriptional response, which boosts mitochondrial activity in times of energy needs and attenuates it when energy demands are low. Reversible acetylation has emerged as a key way to alter PGC-1alpha activity. Although it is well established that PGC-1alpha is deacetylated and activated by Sirt1 and acetylated and inhibited by GCN5, less is known regarding how these enzymes themselves are regulated. Recently, it became clear that the energy sensor, AMP-activated kinase (AMPK) translates the effects of energy stress into altered Sirt1 activity by regulating the intracellular level of its co-substrate nicotinamide adenine dinucleotide (NAD)(+). Conversely, the enzyme ATP citrate lyase (ACL), relates energy balance to GCN5, through the control of the nuclear production of acetyl-CoA, the substrate for GCN5's acetyltransferase activity. We review here how these metabolic signaling pathways, affecting GCN5 and Sirt1 activity, allow the reversible acetylation-deacetylation of PGC-1alpha and the adaptation of mitochondrial energy homeostasis to energy levels.

Figure 1. Regulation of intracellular NAD⁺ levels

Intracellular NAD⁺ levels are regulated by the balance between NAD⁺ synthesis and consumption. NAD⁺ synthesis can occur either de novo from tryptophan, or via the “salvage pathways” that use Nicotinic Acid (NA), Nicotinamide Riboside, or Nicotinamide (NAM), which is produced by enzymes that produce Nicotinamide. NAD⁺ is consumed by enzymes, such as the sirtuins, CD38, CD157, PARP1 and PARP2, that use it as a substrate for their catalytic reaction and convert it into Nicotinamide. Furthermore the ratio of NAD⁺ to NADH can be modulated by metabolic pathways, such as those activated by AMPK.

Figure 2. ACL generates a nuclear/cytosolic pool of acetyl-CoA in mammals

In times when glucose is around, TCA-derived citrate can be converted into aceteyl-CoA by ACL, both in the nucleus and cytosol, thereby providing a nuclear/cytosolic pool of acetyl-CoA. This pool of acetyl-CoA, which seems to be independent of the mitochondrial acetyl-CoA pool, is used for histone acetylation by histone acetyltransferases, such as GCN5.

Figure 3. Energy sensing mediated by cofactors

In times of high energy demand, an AMPK-mediated increase in NAD⁺ activates Sirt1 resulting in the deacetylation and activation of PGC-1α leading ultimately to mitochondrial biogenesis and improved mitochondrial function. Conversely, GCN5-mediated acetylation inactivates PGC-1α when plenty of energy is around. The acetyl-CoA necessary for this acetylation reaction is provided by ACL, which acts as rate limiting for this reaction.