Abstract
Acetylation, as a post-translational modification is increasingly recognized as a nutrient-level dependent modulatory event in the control of cellular function. Non-enzymatic and enzymatic mechanisms appear to function in facilitating this modification of protein lysine residues. The functional role of protein acetylation was originally linked to lifespan regulation in simple organisms under the control of sirtuin deacetylase enzymes. In higher organisms this regulatory system is evolved to modulate in diverse cellular functions and is operational in multiple subcellular compartments. In this chapter the role of acetylation and its regulatory control is explored in the context of the control of mitochondrial integrity and metabolic functioning. Moreover, the concept that protein acetylation may function as a nutrient sensor to ‘fine-tune’ mitochondrial function as an underpinning of cardiac pathology will be explored.
Keywords
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Fox CS, Coady S, Sorlie PD et al (2007) Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 115:1544–1550
Hossain P, Kawar B, El Nahas M (2007) Obesity and diabetes in the developing world–a growing challenge. N Engl J Med 356:213–215
Sack MN (2009) Type 2 diabetes, mitochondrial biology and the heart. J Mol Cell Cardiol 46:842–849
Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11:31–39
Wende AR, Abel ED (2010) Lipotoxicity in the heart. Biochim Biophys Acta 1801:311–319
Zhao S, Xu W, Jiang W et al (2010) Regulation of cellular metabolism by protein lysine acetylation. Science 327:1000–1004
Webster BR, Scott I, Traba J et al (2014) Regulation of autophagy and mitophagy by nutrient availability and acetylation. Biochim Biophys Acta 1841:525–534
Rathmell JC, Newgard CB (2009) Biochemistry. A glucose-to-gene link. Science 324:1021–1022
Wellen KE, Hatzivassiliou G, Sachdeva UM et al (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–1080
Kim SC, Sprung R, Chen Y et al (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23:607–618
Kendrick AA, Choudhury M, Rahman SM et al (2011) Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem J 433:505–514
Xiong Y, Guan KL (2012) Mechanistic insights into the regulation of metabolic enzymes by acetylation. J Cell Biol 198:155–164
Goldrick RB, Hirsch J (1964) Serial studies on the metabolism of human adipose tissue. II. Effects of caloric restriction and refeeding on lipogenesis, and the uptake and release of free fatty acids in obese and nonobese individuals. J Clin Invest 43:1793–1804
Jiang H, Khan S, Wang Y et al (2013) SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496:110–113
Du J, Zhou Y, Su X et al (2011) Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334:806–809
Peng C, Lu Z, Xie Z et al (2011) The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics 10(M111):012658
Park J, Chen Y, Tishkoff DX et al (2013) SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 50:919–930
Paik WK, Pearson D, Lee HW et al (1970) Nonenzymatic acetylation of histones with acetyl-CoA. Biochim Biophys Acta 213:513–522
Scott I, Webster BR, Li JH et al (2012) Identification of a molecular component of the mitochondrial acetyl transferase program; a novel role for GCN5L1. Biochem J 443:627–634
Wagner GR, Payne RM (2013) Widespread and enzyme-independent Nepsilon-acetylation and Nepsilon-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J Biol Chem 288:29036–29045
Muoio DM, Noland RC, Kovalik JP et al (2012) Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab 15:764–777
Schrenk DF, Bisswanger H (1984) Measurements of electron spin resonance with the pyruvate dehydrogenase complex from Escherichia coli. Studies on the allosteric binding site of acetyl-coenzyme A. Eur J Biochem 143:561–566
Ghanta S, Grossman R, Brenner C (2013) Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: chemical and metabolic logic of acetyl-lysine modifications. Crit Rev Biochem Mol Biol 48(6):561–74
Hebert AS, Dittenhafer-Reed KE, Yu W et al (2013) Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell 49:186–199
Lu Z, Scott I, Webster BR et al (2009) The emerging characterization of lysine residue deacetylation on the modulation of mitochondrial function and cardiovascular biology. Circ Res 105:830–841
Riccio A (2010) New endogenous regulators of class I histone deacetylases. Sci Signal 3:pe1
Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126–2128
Lin SJ, Kaeberlein M, Andalis AA et al (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418:344–348
Bitterman KJ, Anderson RM, Cohen HY et al (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277:45099–45107
Anderson RM, Bitterman KJ, Wood JG et al (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423:181–185
Lin SJ, Ford E, Haigis M et al (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18:12–16
Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273:793–798
Sack MN, Finkel T (2012) Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harb Perspect Biol 4
Philp A, Chen A, Lan D et al (2011) Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise. J Biol Chem 286:30561–30570
Scott I, Webster BR, Chan CK et al (2014) GCN5-like Protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy. J Biol Chem 289:2864–2872
Balasse EO, Fery F (1989) Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev 5:247–270
Fan J, Shan C, Kang HB et al (2014) Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex. Mol Cell 53:534–548
Anderson RM, Bitterman KJ, Wood JG et al (2002) Manipulation of a nuclear NAD + salvage pathway delays aging without altering steady-state NAD + levels. J Biol Chem 277:18881–18890
Dioum EM, Chen R, Alexander MS et al (2009) Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324:1289–1293
Revollo JR, Grimm AA, Imai S (2007) The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Curr Opin Gastroenterol 23:164–170
Ito Y, Yonekura R, Maruta K et al (2003) Tryptophan metabolism was accelerated by exercise in rat. Adv Exp Med Biol 527:531–535
Shin M, Ohnishi M, Sano K et al (2003) NAD levels in the rat primary cultured hepatocytes affected by peroxisome-proliferators. Adv Exp Med Biol 527:653–658
Revollo JR, Grimm AA, Imai S (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 279:50754–50763
Berger F, Lau C, Dahlmann M et al (2005) Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem 280:36334–36341
Yang H, Yang T, Baur JA et al (2007) Nutrient-sensitive mitochondrial NAD + levels dictate cell survival. Cell 130:1095–1107
Gomes AP, Price NL, Ling AJ et al (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638
Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460:587–591
Webster BR, Lu Z, Sack MN et al (2012) The role of sirtuins in modulating redox stressors. Free Radic Biol Med 52:281–290
Verdin E, Hirschey MD, Finley LW et al (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35:669–675
Wu Z, Puigserver P, Andersson U et al (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124
Lehman JJ, Barger PM, Kovacs A et al (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856
Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem 280:16456–16460
Rodgers JT, Lerin C, Haas W et al (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118
Rodgers JT, Puigserver P (2007) Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A 104:12861–12866
Erion DM, Ignatova ID, Yonemitsu S et al (2009) Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein. Cell Metab 10:499–506
Gerhart-Hines Z, Rodgers JT, Bare O et al (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 26:1913–1923
Purushotham A, Schug TT, Xu Q et al (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9:327–338
Dietrich MO, Antunes C, Geliang G et al (2010) Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci 30:11815–11825
Alcendor RR, Gao S, Zhai P et al (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100:1512–1521
Pfluger PT, Herranz D, Velasco-Miguel S et al (2008) Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 105:9793–9798
Hasegawa K, Wakino S, Yoshioka K et al (2010) Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 285:13045–13056
Herranz D, Munoz-Martin M, Canamero M et al (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1:3
Nadtochiy SM, Redman E, Rahman I et al (2011) Lysine deacetylation in ischaemic preconditioning: the role of SIRT1. Cardiovasc Res 89:643–649
Lombard DB, Alt FW, Cheng HL et al (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27:8807–8814
Bao J, Lu Z, Joseph JJ et al (2010) Characterization of the murine SIRT3 mitochondrial localization sequence and comparison of mitochondrial enrichment and deacetylase activity of long and short SIRT3 isoforms. J Cell Biochem 110:238–247
Scher MB, Vaquero A, Reinberg D (2007) SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev 21:920–928
Sundaresan NR, Samant SA, Pillai VB et al (2008) SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 28:6384–6401
Kong X, Wang R, Xue Y et al (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5:e11707
Lombard DB, Zwaans BM (2014) SIRT3: as simple as it seems? Gerontology 60:56–64
Hirschey MD, Shimazu T, Goetzman E et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125
Someya S, Yu W, Hallows WC et al (2010) Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143:802–812
Hirschey MD, Shimazu T, Jing E et al (2011) SIRT3 Deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44(2):177–190
Chen Y, Zhang J, Lin Y et al (2011) Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep 12(6):534–541
Lu Z, Bourdi M, Li JH et al (2011) SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity. EMBO Rep 12:840–846
Hallows WC, Yu W, Smith BC et al (2011) Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 41:139–149
Ahn BH, Kim HS, Song S et al (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 105:14447–14452
Bao J, Scott I, Lu Z et al (2010) SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity. Free Radic Biol Med 49:1230–1237
Tao R, Coleman MC, Pennington JD et al (2010) Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 40:893–904
Hafner AV, Dai J, Gomes AP et al (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2:914–923
Palacios OM, Carmona JJ, Michan S et al (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging (Albany NY) 1:771–783
Sundaresan NR, Gupta M, Kim G et al (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119:2758–2771
Sack MN, Rader TA, Park S et al (1996) Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94:2837–2842
Lopaschuk GD, Ussher JR, Folmes CD et al (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258
Wagner GR, Pride PM, Babbey CM et al (2012) Friedreich’s ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase. Hum Mol Genet 21:2688–2697
Nguyen TT, Wong R, Menazza S et al (2013) Cyclophilin D modulates mitochondrial acetylome. Circ Res 113:1308–1319
Karamanlidis G, Lee CF, Garcia-Menendez L et al (2013) Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 18:239–250
Still AJ, Floyd BJ, Hebert AS et al (2013) Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation. J Biol Chem 288:26209–26219
Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell 31:449–461
Jing E, O′neill BT, Rardin MJ et al (2013) Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 62:3404–3417
Bharathi SS, Zhang Y, Mohsen AW et al (2013) Sirtuin 3 (SIRT3) Protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J Biol Chem 288:33837–33847
Samant SA, Zhang HJ, Hong Z et al (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34:807–819
Tseng AH, Shieh SS, Wang DL (2013) SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med 63:222–34
Webster BR, Scott I, Han K et al (2013) Restricted mitochondrial protein acetylation initiates mitochondrial autophagy. J Cell Sci 126:4843–4849
Papa L, Germain D (2013) SirT3 regulates a novel arm of the mitochondrial unfolded protein response. Mol Cell Biol 34(4):699–710
Norris KL, Lee JY, Yao TP (2009) Acetylation goes global: the emergence of acetylation biology. Sci Signal 2(97):pe76
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Sack, M.N. (2014). Acetylation in the Control of Mitochondrial Metabolism and Integrity. In: Lopaschuk, G., Dhalla, N. (eds) Cardiac Energy Metabolism in Health and Disease. Advances in Biochemistry in Health and Disease, vol 11. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1227-8_8
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1227-8_8
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-1226-1
Online ISBN: 978-1-4939-1227-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)