Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility.
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.
Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratory of Integrative and Systems Physiology, Lausanne, Switzerland.
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EH
Jeninga
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Schoonjans
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J
Auwerx
D000107:Acetylation; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1