Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Pietrocola, Federico; Galluzzi, Lorenzo; Pedro, José Manuel Bravo-San; Madeo, Frank; Kroemer, Guido

doi:10.1016/j.cmet.2015.05.014

Cited by 1,083 publications

(951 citation statements)

References 145 publications

Supporting

Mentioning

926

Contrasting

Unclassified

Order By: Relevance

“…In particular, emerging data highlight the importance of mitochondrial acetyl-CoA levels as a major contributor to nonenzymatic acetylation in mitochondrial proteins, as well as a cofactor for acetyltransferase (37,48). Although we could not evaluate the mitochondrial acetyl-CoA levels in the current study, 95% of CoA, an essential cofactor for acetyl-CoA, is known to be localized to the mitochondria in terms of its overall intracellular content (12).…”

Section: H359 Acetylation Control Of Energy Metabolism In the Newbornmentioning

confidence: 84%

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Fukushima

Alrob

Zhang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Fukushima A, Alrob OA, Zhang L, Wagg CS, Altamimi T, Rawat S, Rebeyka IM, Kantor PF, Lopaschuk GD. Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am J Physiol Heart Circ Physiol 311: H347-H363, 2016. First published June 3, 2016; doi:10.1152/ajpheart.00900.2015.-Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid ␤-oxidation rates increased in 21-day vs. 1-and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and ␤-hydroxyacylCoA dehydrogenase (␤-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid ␤-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and ␤-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-␥ coactivator-1␣, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxiainducible factor-1␣, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation.Listen to this article's corresponding podcast at http://ajpheart.podbean. com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/. myocardial fatty acid oxidation; lysine acetylation; lysine succinylation; newborn heart NEW & NOTEWORTHYThe present study is the first showing that alterations in acetylation and succinylation control of metabolic enzymes contribute to the dramatic shift in cardiac energy metabolism from glycolysis to fatty acid ␤-oxidation seen during maturation. Our results suggest that lysine acetylation enhances cardiac fatty acid ␤-oxidation and inhibits glycolysis during maturation.OVER 1% OF NEWBORNS ARE DIAGNOSED with congenital heart disease (CHD), with one-third of these needing surgery within the first months of life (36). Despite the major advance...

show abstract

Section: H359 Acetylation Control Of Energy Metabolism In the Newbornmentioning

confidence: 84%

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Fukushima

Alrob

Zhang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Accordingly, histone acetylation is intimately associated with the cellular acetyl-CoA pool in response to metabolic state as it depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment. 20,[42][43][44][45][46] The fact that the mutation of a single BRCA1 allele dramatically alters the metabolomic signature of normal-like breast epithelial cells to induce a significant >20-fold augmentation of acetyl-CoA 41 supports the notion that this model of BRCA1 haploinsufficiency might be relevant to directly explore:…”

mentioning

confidence: 83%

Metformin targets histone acetylation in cancer-prone epithelial cells

et al. 2016

View full text Add to dashboard Cite

The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy. KEYWORDS BRCA1; epigenetics; histone acetylation; metformin; mitochondria While metabolic rewiring of cancer cells can be a direct consequence of the concerted action of oncogenes and tumor suppressor genes that drive aberrant growth of cancer tissues, altered metabolism might also play a primary, causative role in oncogenesis. Accordingly, metabolic reprogramming is increasingly appreciated as a candidate hallmark of tumorigenesis. [1][2][3][4][5] In a recently proposed metabolism-centered model of carcinogenesis, known as geroncogenesis 2 the possibility of acquiring genetic aberrations increases when aging itself operates as a driver of cancer-like metabolic landscapes. Tumor formation might therefore depend not only on accumulating mutations in the genome, but also on the decline in the homeostasis or metabolic health that naturally occurs in aging cells. Indeed, after many years of being subordinated to the nucleus as the commander-in-chief, able to initiate biological events, the capacity of metabolism to independently dictate cellular actions is increasingly recognized among most cell biologists. Accordingly, the research community now acknowledges that aging-driven alteration of metabolic homeostasis might be sufficient to favor an imbalance in self-amplifying metabolic landscapes that ultimately manifest as aging-driven diseases, including cancer. 6Metabolic programs: From anabolic supporters of genomic instability to epigenetic regulators of carcinogenesisThe metabolic health of our cells might be a key determinant factor pushing the risk balance or cancer risk-meter toward health or the risk of cancer.1,2 On the one hand, genomic instability, a charac...

show abstract

“…Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate that modulates the balance of anabolism and catabolism by functioning as the fuel for energy generation or as the precursor of lipogenesis for energy storage in many organisms (1). Acetyl-CoA is also deemed a second messenger for physiological regulation by supplying an acetyl group for protein acetylation (1,2), an important mechanism of post-translational modification (PTM).…”

mentioning

confidence: 99%

Cyclic AMP Inhibits the Activity and Promotes the Acetylation of Acetyl-CoA Synthetase through Competitive Binding to the ATP/AMP Pocket

Han

Shen

Wang

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Ruma BanerjeeThe high-affinity biosynthetic pathway for converting acetate to acetyl-coenzyme A (acetyl-CoA) is catalyzed by the central metabolic enzyme acetyl-coenzyme A synthetase (Acs), which is finely regulated both at the transcriptional level via cyclic AMP (cAMP)-driven trans-activation and at the post-translational level via acetylation inhibition. In this study, we discovered that cAMP directly binds to Salmonella enterica Acs (SeAcs) and inhibits its activity in a substrate-competitive manner. In addition, cAMP binding increases SeAcs acetylation by simultaneously promoting Pat-dependent acetylation and inhibiting CobB-dependent deacetylation, resulting in enhanced SeAcs inhibition. A crystal structure study and site-directed mutagenesis analyses confirmed that cAMP binds to the ATP/AMP pocket of SeAcs, and restrains SeAcs in an open conformation. The cAMP contact residues are well conserved from prokaryotes to eukaryotes, suggesting a general regulatory mechanism of cAMP on Acs.Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate that modulates the balance of anabolism and catabolism by functioning as the fuel for energy generation or as the precursor of lipogenesis for energy storage in many organisms (1). Acetyl-CoA is also deemed a second messenger for physiological regulation by supplying an acetyl group for protein acetylation (1, 2), an important mechanism of post-translational modification (PTM). Acetyl-coenzyme A synthetase (Acs) 5 (EC 6.2

show abstract

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Cited by 1,083 publications

References 145 publications

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Metformin targets histone acetylation in cancer-prone epithelial cells

Cyclic AMP Inhibits the Activity and Promotes the Acetylation of Acetyl-CoA Synthetase through Competitive Binding to the ATP/AMP Pocket

Contact Info

Product

Resources

About