Aula 8 - Acetyl-CoA

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com
Cell Metabolism
Review
Acetyl Coenzyme A: A Central

Metabolite and Second Messenger
Federico Pietrocola,1,2,3,4,5,10 Lorenzo Galluzzi,1,2,3,4,6,10 José Manuel Bravo-San Pedro,1,2,3,4,6 Frank Madeo,7,8,*
and Guido Kroemer1,2,3,4,5,9,*
1Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France
2INSERM U1138, 75006 Paris, France
3Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006 Paris, France
4Université Pierre et Marie Curie/Paris VI, 75006 Paris, France
5Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France
6Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France
7Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
8BioTechMed-Graz, 8010 Graz, Austria
9Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
10Co-first author
*Correspondence: [email protected] (F.M.), [email protected] (G.K.)

http://dx.doi.org/10.1016/j.cmet.2015.05.014
Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct

subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentra-
tions influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering
substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones,
acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both
directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance
between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and
as a second messenger.
Introduction Nonetheless, acetylation is mostly studied as a post-transla-

Acetyl-coenzyme A (acetyl-CoA) is so central for intermediate tional modification that concerns the Nε amino group of lysine
metabolism that hypothetical reconstructions of the origin of residues, eliminating their positive charge and increasing sterical
life postulate its involvement in ancestral methanotrophic reac- hindrance (Choudhary et al., 2014). Thus, Nε acetylation can alter
tions performed by the last common precursor of prokaryotes the functional profile of a specific protein by influencing its cata-
(Nitschke and Russell, 2013). From archaebacteria to mamma- lytic activity, its capacity to interact with other molecules
lians, acetyl-CoA occupies a critical position in multiple cellular (including other proteins), its subcellular localization, and/or its
processes, as a metabolic intermediate, as a precursor of stability (Choudhary et al., 2014). These effects can directly orig-
anabolic reactions, as an allosteric regulator of enzymatic activ- inate from the changes in charge and hindrance imposed by Nε
ities, and as a key determinant of protein acetylation (Choudh- acetylation, or they can reflect (1) the binding of proteins that
ary et al., 2014). Acetyl-CoA is indeed the actual molecule contain acetyl-lysine recognition bromodomains (Zeng et al.,
through which glycolytic pyruvate enters the tricarboxylic acid 2010) or (2) the occupancy of lysine residues that may have
(TCA) cycle, is a key precursor of lipid synthesis, and is the been subjected to other post-translational modifications,
sole donor of the acetyl groups for acetylation (Choudhary including ubiquitination, methylation, formylation, and higher-
et al., 2014). order acylation reactions (Choudhary et al., 2014).
Acetyl-CoA is a membrane-impermeant molecule constituted Nε acetylation can occur through a non-enzymatic mecha-
by an acetyl moiety (CH3CO) linked to coenzyme A (CoA), a de- nism, especially in alkaline environments like the mitochondrial
rivative of vitamin B5 and cysteine, through a thioester bond (Shi matrix (Weinert et al., 2014), or can be catalyzed by a diverse
and Tu, 2015). As thioester bonds are energy rich, the chemical group of lysine acetyltransferases (KATs) (Choudhary et al.,
structure of acetyl-CoA facilitates the transfer of the acetyl moi- 2014). The human genome encodes no less than 22 distinct
ety to a variety of acceptor molecules, including amino groups on KATs, which possess marked substrate specificity (Davenport
proteins (Shi and Tu, 2015). Acetylation can occur as a co-trans- et al., 2014). Many KATs have a relatively high KD (low affinity)
lational event. In this setting, Na acetyltransferases (NATs) trans- for acetyl-CoA, meaning that physiological fluctuations in the
fer an acetyl group from acetyl-CoA to the a-amino group of abundance of acetyl-CoA within the cellular compartment where
the N-terminal residue of the protein (which generally is serine, such KATs are expressed can affect their catalytic activity. For
alanine, glycine, threonine, valine, or cysteine), once the initiator instance, KAT2A (also known as GCN5) has a KD for acetyl-
methionine has been removed by methionine aminopeptidases. CoA of 0.56 mM and its yeast counterparts of 8.5 mM (Langer
N-terminal acetylation affects the vast majority of human pro- et al., 2002), both of which fall in the concentration range of
teins, determining their stability, localization, and function (Holle- acetyl-CoA found in human or yeast cells (Cai et al., 2011; Lee
beke et al., 2012). et al., 2014). Other KATs have a similar affinity for acetyl-CoA
Cell Metabolism 21, June 2, 2015 ª2015 Elsevier Inc. 805

Licenciado para - Paulo Sérgio Martins dos Santos - 09609690718 - Protegido por Eduzz.com
Cell Metabolism
Review
and CoA, meaning that their activity is regulated by the relative 2012). These regulation circuitries ensure that the products of
abundance of acetyl-CoA and CoA (the latter can mediate prod- glycolysis are employed for ATP generation when cells are in
uct inhibition). Importantly, the concentration of acetyl-CoA (or energy-low conditions (characterized by elevated ADP, NAD+,
the acetyl-CoA/CoA ratio) does not only determine the enzy- and CoA levels), but diverted toward anabolic metabolism
matic activity of KATs, but also alters their specificity. Thus, when the energy stores are repleted (characterized by elevated
KATs like E1A binding protein p300 (EP300) and CREB binding ATP, NADH, and acetyl-CoA levels).
protein (CREBBP, best known as CBP) exhibit distinct Hill values Alternatively, acetyl-CoA can be generated as the end prod-
(i.e., different degrees of cooperativity) at varying acetyl-CoA uct of b-oxidation. In this case, one among several members of
levels, meaning that their selectivity (i.e., their preference to acet- the acyl-CoA synthetase protein family catalyzes the CoA- and
ylate distinct lysine residues) changes (Denisov and Sligar, 2012; ATP-dependent conversion of cytosolic free fatty acids into
Henry et al., 2015). acyl-CoA. Acyl-CoA is then condensed with L-carnitine to
In response to a series of physiological or pathological condi- form acylcarnitine and free CoA, a cytosolic reaction catalyzed
tions, the abundance and/or distribution of acetyl-CoA in distinct by carnitine palmitoyltransferase 1 (CPT1). Acylcarnitine is im-
subcellular and/or pericellular compartments changes consider- ported into mitochondria through the antiporter solute carrier
ably. Thus, acetyl-CoA can act as a second messenger that re- family 25 (carnitine/acylcarnitine translocase), member 20
lays signals from the extracellular to the intracellular milieu. (SLC25A20), which exchanges it for free L-carnitine. Finally,
This may contribute to the elevated variability in lysine acetyla- mitochondrial acylcarnitine is reconverted by carnitine palmi-
tion patterns encountered in organs and subcellular fractions in toyltransferase 2 (CPT2) into L-carnitine (which drives the
distinct functional states (Lundby et al., 2012). so-called ‘‘carnitine shuttle’’) and acyl-CoA, and the latter un-
Here, we discuss the ability of acetyl-CoA to regulate adaptive dergo b-oxidation to generate NADH and acetyl-CoA for use
responses to homeostatic perturbations by controlling the as direct and indirect, respectively, respiratory substrates
equilibrium between catabolic and anabolic reactions as well (Rufer et al., 2009).
as by influencing major cellular processes such as cell cycle pro- Branched-chain amino acids (i.e., valine, leucine, and isoleu-
gression, mitosis, autophagy, and regulated cell death (RCD). cine) can also be employed to produce acetyl-CoA (Harris
et al., 2005), a molecular circuitry that may depend on the mito-
Acetyl-CoA: A Central Metabolite chondrial deacetylase sirtuin 3 (SIRT3), at least in some tissues
Acetyl-CoA is not only the product of multiple catabolic reac- (including the brain, liver, kidney, and skeletal muscles) (Ditten-
tions, but also one of the central substrates for anabolic hafer-Reed et al., 2015). To this aim, branched amino acids
metabolism. For illustrative purposes, we will discuss the mito- must be first transaminated to branched-chain a-ketoacids, a
chondrial and extramitochondrial metabolism of acetyl-CoA reaction that can be catalyzed by the cytosolic enzyme
separately. branched-chain amino acid transaminase 1 (BCAT1). Upon
Generation of Mitochondrial Acetyl-CoA import into the mitochondrial matrix via the carnitine shuttle
In most mammalian cells, acetyl-CoA is predominantly gener- (see below) (Violante et al., 2013), branched-chain a-ketoacids
ated in the mitochondrial matrix by various metabolic circuitries, are processed via a multi-step reaction comparable to the decar-
namely glycolysis, b-oxidation, and the catabolism of branched boxylation of pyruvate. This irreversible reaction is catalyzed by
amino acids (Figure 1A). the mitochondrial branched-chain a-ketoacid dehydrogenase
Glycolysis culminates in the generation of cytosolic pyruvate, (BCKD) complex, a large multicomponent enzymatic system
which is imported into mitochondria by the mitochondrial pyru- yielding NADH, acetyl-CoA, and other acyl-CoA thioesters
vate carrier (MPC), a heterodimer of MPC1 and MPC2 (Herzig (which can be processed by b-oxidation or the TCA) as end prod-
et al., 2012). Mitochondrial pyruvate is decarboxylated to form ucts (Harris et al., 2005). Of note, some mammalian cells express
acetyl-CoA, CO2, and NADH by the so-called pyruvate dehydro- a mitochondrial variant of BCAT1 (i.e., BCAT2), which is catalyt-
genase complex (PDC), a large multicomponent system that in ically active (Yennawar et al., 2006). However, how branched-
humans is composed of (1) three proteins that are directly chain amino acids enter the mitochondrial matrix has not been
involved in CoA- and NAD+-dependent pyruvate decarboxyl- determined yet.
ation, i.e., pyruvate dehydrogenase (lipoamide) (PDH, which in In addition to these nearly ubiquitous metabolic circuitries,
exists in three isoforms), dihydrolipoamide S-acetyltransferase there are organ-specific pathways for mitochondrial acetyl-
(DLAT), and dihydrolipoamide dehydrogenase (DLD); (2) two reg- CoA generation. For instance, neurons can employ the ketone
ulatory components, i.e., pyruvate dehydrogenase kinase (PDK, body D-b-hydroxybutyrate to generate acetyl-CoA (Cahill,
which also exists in four isoforms) and pyruvate dehydrogenase 2006). This occurs via a three-step reaction involving the
phosphatase (PDP, a heterodimer involving either of two cata- NAD+-dependent oxidation of D-b-hydroxybutyrate to acetoa-
lytic subunits and either of two regulatory subunits); and (3) cetate (catalyzed by 3-hydroxybutyrate dehydrogenase, type
one non-enzymatic subunit, i.e., pyruvate dehydrogenase com- 1, BDH1), the transfer of CoA from succinyl-CoA to acetoacetate
plex, component X (PDHX) (Patel et al., 2014). Importantly, both (catalyzed by 3-oxoacid CoA transferase 1, OXCT1, or OXCT2),
acetyl-CoA and NADH as well as ATP allosterically inhibit PDC as and the CoA-dependent cleavage of acetoacetyl-CoA into two
they activate PDK. Conversely, CoA, NAD+, and ADP promote acetyl-CoA molecules (catalyzed by an enzymatic complex
pyruvate decarboxylation by inhibiting PDK. Finally, acetyl-CoA with acetoacetyl-CoA thiolase activity) (Cahill, 2006). Of note, it
acts as a potent allosteric activator of pyruvate carboxylase has recently been demonstrated that the acetylation pattern of
(PC), another pyruvate-consuming enzyme that synthesizes mitochondrial proteins, as controlled by SIRT3, is crucial for
oxaloacetate for anaplerotic reactions (Adina-Zada et al., mice that respond to starvation to increase the hepatic synthesis
806 Cell Metabolism 21, June 2, 2015 ª2015 Elsevier Inc.

Cell Metabolism
Review
Figure 1. Mitochondrial and Nucleo-Cytosolic Bioenergetic Metabolism of Acetyl-CoA in Mammalian Cells

(A–D) Acetyl coenzyme A (acetyl-CoA) is a key metabolic intermediate. Generally, the majority of cellular acetyl-CoA is generated (A) and consumed (C) in the
mitochondrial matrix, in the context of the oxidative metabolism of glycolytic pyruvate (Pyr), free fatty acids (FFAs), branched-chain amino acids (BCAAs), or
ketone bodies within the tricarboxylic acid (TCA) cycle. Acetyl-CoA can also be generated in the cytosolic compartment (B), where it supports several anabolic
reactions, including lipogenesis, steroidogenesis, and the synthesis of specific amino acids (D). In some malignant cells, the pyruvate dehydrogenase complex
(PDC), ATP citrate lyase (ACLY), and acyl- CoA synthetase short-chain family, member 2 (ACSS2) are also found in the nucleus and produce acetyl-CoA therein.
Of note, both mitochondrial and nucleo-cytosolic acetyl-CoA pools are critically involved in protein acetylation reactions. ACAA2, acetyl-CoA acyltransferase 2;
ACAC, acetyl-CoA carboxylase; ACAD, acyl-CoA dehydrogenase; ACAT1, acetyl-CoA carboxylase 1; ACAT2, acetyl-CoA acetyltransferase 2; Ace, acetate; Ach,
acetaldehyde; ACO1, aconitase 1, soluble; ACSS1, acyl-CoA synthetase short-chain family, member 1; ADH1B, alcohol dehydrogenase IB (class I), beta
polypeptide; ALDH1A1, aldehyde dehydrogenase 1 family, member A1; ALDH2, aldehyde dehydrogenase 2 family; BCAT1, branched chain amino-acid
transaminase 1, cytosolic; BCAT2, branched chain amino-acid transaminase 2, mitochondrial; BCKD, branched-chain a-ketoacid dehydrogenase; BDH1,
3-hydroxybutyrate dehydrogenase, type 1; b-OHB, D-b-hydroxybutyrate; Cit, citrate; CPT1, carnitine palmitoyltransferase 1; CPT2, carnitine palmitoyl-
transferase 2; ECH, enoyl-CoA hydratase; ER, endoplasmic reticulum; Eth, ethanol; FASN, fatty acid synthase; Gln, glutamine; GLS, glutaminase; GLUD1,
glutamate dehydrogenase 1; GOT1, glutamic-oxaloacetic transaminase 1, soluble; HADH, hydroxyacyl-CoA dehydrogenase; HAT, histone acetyltransferase;
HMGCL, 3-hydroxymethyl-3-methylglutaryl-CoA lyase; HMGCR, 3-hydroxy-3-methyl-glutaryl-CoA reductase; HMGCS1, 3-hydroxy-3-methylglutaryl-CoA
synthase 1, HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2, IDH1, isocitrate dehydrogenase 1; KAT, lysine acetyltransferase; MPC1, mitochondrial
pyruvate carrier 1; MPC2, mitochondrial pyruvate carrier 2; NAT, Na acetyltransferase; NEA, non-enzymatic acetylation; OXCT, 3-oxoacid CoA transferase.
of ketone bodies (which relies on acetyl-CoA, see below) while ethanol ingestion causes protein acetylation preferentially in he-
activating bioenergetic pathways that utilize ketone bodies in patic mitochondria (Fritz et al., 2013).
extrahepatic tissues (Dittenhafer-Reed et al., 2015). Hepato- Generation of Cytosolic Acetyl-CoA
cytes can also obtain acetyl-CoA from ethanol (Cederbaum, In physiological and normoxic conditions, glycolysis- or b-oxida-
2012; Lundquist et al., 1962). In this case, ethanol is first con- tion-derived mitochondrial acetyl-CoA represents the major
verted into acetaldehyde in the cytosol by alcohol dehydroge- source of cytosolic acetyl-CoA upon transportation (see below).
nase IB (class I) beta polypeptide (ADH1B). Acetaldehyde freely That said, there are at least two relatively ubiquitous metabolic
diffuses to the mitochondrial matrix, where it is converted into circuitries through which cells actually produce acetyl-CoA in
acetate by aldehyde dehydrogenase 2 family (ALDH2). Finally, the cytosol (Figure 1B).
the mitochondrial enzyme acyl-CoA synthetase short-chain fam- First, cytosolic acetyl-CoA can originate from glutamine
ily, member 1 (ACSS1) employs acetate to produce acetyl-CoA reductive carboxylation, especially when glycolysis is blocked
(Fujino et al., 2001). This metabolic circuitry may explain why (Yang et al., 2014), in hypoxic conditions (Metallo et al., 2012),

Cell Metabolism
Review
or in the presence of mitochondrial defects (Mullen et al., 2012). vate (Sutendra et al., 2014). Nuclear PDC levels as well as
Upon uptake from the extracellular milieu (which is mediated by histone 3 (H3) acetylation increase upon the administration of
various transporters, depending on cell type), cytosolic gluta- epidermal growth factor (EGF), whereas the inhibition of EGF
mine is metabolized by glutaminase (GLS) to generate gluta- receptor (EGFR) signaling limits nuclear PDC accumulation
mate, which enters mitochondria through the H+-dependent concomitant with a reduction in H3 acetylation levels. Also, the
glutamate/aspartate antiporter solute carrier family 25 (aspar- inhibition of respiratory complex I with rotenone can promote
tate/glutamate carrier), member 13 (SLC25A13). Mitochondrial the mitochondrio-nuclear relocalization of PDC, a process that
glutamate is converted into a-ketoglutarate (a reaction catalyzed appears to require heat shock 70 kDa protein 1A (HSPA1A)
by glutamate dehydrogenase 2, GLUD2, or glutamic-oxaloacetic (Sutendra et al., 2014). However, the exact mechanisms through
transaminase 2, mitochondrial, GOT2), which undergoes reduc- which PDC is exported from mitochondria and enters the nu-
tive carboxylation within the TCA cycle to generate citrate. cleus remain enigmatic. Since PDK is not detectable within
Finally, citrate can be exported back to the cytosol via the dicar- nuclei (Sutendra et al., 2014), nuclear PDC may be constitutively
boxylate antiporter solute carrier family 25 (mitochondrial carrier; derepressed to support histone acetylation and cell cycle
citrate transporter), member 1 (SLC25A1), and converted into progression. Interestingly, two other acetyl-CoA-generating en-
oxaloacetate and acetyl-CoA by ATP citrate lyase (ACLY) (Zaidi zymes, namely ACLY and ACSS2, have been localized to the nu-
et al., 2012). Of note, glutamate also can be converted into a-ke- cleus and linked to cell growth and proliferation (Comerford
toglutarate by GLUD1, a cytosolic variant of GLUD2, at least in et al., 2014; Takahashi et al., 2006; Wellen et al., 2009). Taken
some settings (Grassian et al., 2014). Along similar lines, a cyto- together, these observations suggest that, even though acetyl-
solic form of GOT2 (i.e., GOT1) can catalyze the reversible inter- CoA freely diffuses between the cytosol and nucleus, the pro-
conversion of glutamate and oxaloacetate into a-ketoglutarate duction of acetyl-CoA in the proximity of histones may favor
and aspartate. Cytosolic a-ketoglutarate can be metabolized the activation of epigenetic programs associated with cell
by isocitrate dehydrogenase 1 (IDH1) and aconitase 1 soluble growth (see below).
(ACO1) to generate citrate for acetyl-CoA synthesis by ACLY Metabolic Fate of Mitochondrial Acetyl-CoA
(Grassian et al., 2014). Normally, mitochondrial acetyl-CoA is metabolized within the
Second, a cytosolic counterpart of ACSS1, i.e., acyl-CoA syn- TCA to yield NADH, the main substrate for ATP synthesis via
thetase short-chain family, member 2 (ACSS2), employs acetate oxidative phosphorylation (Boroughs and DeBerardinis, 2015).
to produce acetyl-CoA in an ATP-dependent manner (Schug Some cells, however, including hepatocytes, can employ mito-
et al., 2015). Cytosolic acetate can derive from the extracellular chondrial acetyl-CoA to synthesize ketone bodies, i.e., acetoa-
milieu, upon uptake by various members of the monocarboxy- cetate, acetone, and D-b-hydroxybutyrate (Newman and Verdin,
late transporter protein family (Halestrap and Price, 1999), or it 2014). This metabolic pathway, which is catalyzed by the
can be synthesized from ethanol-derived acetaldehyde by a sequential activity of the acetoacetyl-CoA thiolase complex,
cytosolic variant of ALDH2, namely aldehyde dehydrogenase 1 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), 3-hy-
family, member A1 (ALDH1A1), at least in hepatocytes (Ceder- droxymethyl-3-methylglutaryl-CoA lyase (HMGCL), and BDH1,
baum, 2012). Although circulating acetate levels are relatively is particularly active in conditions of fasting or caloric restriction,
low in modern humans (as compared to their ancestors, owing when the majority of mitochondrial acetyl-CoA derives from
to dietary changes) (Frost et al., 2014), the ACSS2-dependent b-oxidation (Figure 1C) (Newman and Verdin, 2014). Liver-
conversion of acetate into acetyl-CoA has been shown to be pre- derived ketone bodies enter the circulation and are readily taken
ponderant in primary and metastatic malignant cells of various up by neurons and cardiomyocytes, which employ them to pro-
origin (Mashimo et al., 2014), especially in hypoxic conditions duce ATP upon reconversion to acetyl-CoA and entry in the TCA
(Kamphorst et al., 2014; Schug et al., 2015). In line with this (Cotter et al., 2013). Of note, D-b-hydroxybutyrate acts as an
notion, hepatocellular carcinomas driven by the expression of endogenous inhibitor of class I histone deacetylases, i.e.,
simian virus 40 (SV40) T antigen or by v-myc avian myelocytoma- HDAC1, HDAC2, and HDAC3 (Shimazu et al., 2013). This may
tosis viral oncogene homolog (Myc) overexpression combined explain why fasting and caloric restriction increase global his-
with phosphatase and tensin homolog (Pten) inactivation exhibit tone acetylation in some mouse tissues, particularly the liver
reduced growth rate in Acss2 / mice (Comerford et al., 2014). and kidney (Donohoe et al., 2012; Shimazu et al., 2013).
Moreover, elevated ACSS2 levels are associated with high tumor Metabolic Fate of Cytosolic Acetyl-CoA
grade and dismal disease outcome in patients with human Cytosolic acetyl-CoA is the precursor of multiple anabolic reac-
gliomas (Mashimo et al., 2014) and triple-negative breast carci- tions that underlie the synthesis of fatty acids and steroids, as
nomas (Comerford et al., 2014). Thus, the metabolic stress asso- well as specific amino acids including glutamate, proline, and
ciated with malignant transformation and/or tumor progression arginine (Figure 1D). The rate-limiting step of lipogenesis is cata-
(which generally involves decreased nutrient availability and hyp- lyzed by acetyl-CoA carboxylase (ACAC), a biotin-dependent
oxia) may render cancer cells addicted to ACSS2 activity (which enzyme that irreversibly carboxylates acetyl-CoA to malonyl-
is non-oncogenic per se) (Galluzzi et al., 2013). Further corrobo- CoA (Brownsey et al., 2006). The reverse reaction (i.e., the decar-
rating this notion, breast carcinomas often exhibit ACSS2 ampli- boxylation of malonyl-CoA to acetyl-CoA), which is catalyzed by
fications (Schug et al., 2015). malonyl-CoA decarboxylase (MLYCD), not only inhibits lipogen-
Ectopic Acetyl-CoA Generation esis but also stimulates the mitochondrial uptake of free fatty
As malignant cells progress through the S phase of the cell cycle, acids for b-oxidation by relieving the malonyl-CoA-mediated
functional PDC can translocate from mitochondria to the nu- inhibition of CPT1 (Koves et al., 2008). Interestingly, the mus-
cleus, catalyzing the ectopic synthesis of acetyl-CoA from pyru- cle-specific knockout of Mlycd prevents the development of

Cell Metabolism
Review
diet-induced glucose intolerance in mice as it inhibits b-oxidation Conversely, nuclear pores allow acetyl-CoA to freely distribute
(Koves et al., 2008). The human genome codes for two ACAC between the cytosol and the nucleus. Of note, the endoplasmic
isoforms, namely ACACA and ACACB, which are differentially reticulum (ER) does not contain acetyl-CoA-generating en-
expressed in distinct tissues (Travers and Barber, 1997). In zymes, implying that the acetylation of proteins within the ER
energy-low conditions (low ATP, high cyclic AMP levels), ACAC lumen critically depends on the import of acetyl-CoA from the
is inhibited upon phosphorylation by protein kinase, AMP-acti- cytosol. Taken together, these observations suggest that the
vated (PRKA, best known as AMPK). In line with this notion, bioenergetic and signaling functions of acetyl-CoA are finely
the cytosolic pool of acetyl-CoA increases upon AMPK activa- regulated by compartmentalization and inter-organellar acetyl-
tion, at least in yeast (Zhang et al., 2013). Whether a similar effect CoA fluxes, which (at least in part) are influenced by the subcel-
occurs in mammalian cells remains to be confirmed. In mouse lular localization of acetyl-CoA-generating reactions.
hepatocytes, the knockout of both Acaca and Acacb causes Export of Acetyl-CoA from Mitochondria
the hyperacetylation of extramitochondrial proteins (but the hy- The transport of acetyl-CoA from the mitochondrial matrix to the
poacetylation of mitochondrial proteins) (Chow et al., 2014), sug- cytosol heavily relies on the so-called ‘‘citrate-malate-pyruvate
gesting that the utilization of acetyl-CoA for lipogenesis has a shuttle.’’ In this context, mitochondrial acetyl-CoA is condensed
significant impact on acetylation reactions. Spermidine/sper- with oxaloacetate by citrate synthase (CS), the first enzyme of
mine N(1)-acetyltransferase 1 (SAT1) also consumes cytosolic the TCA cycle, generating citrate and free CoA. Citrate can be
acetyl-CoA as it acetylates polyamines (i.e., spermidine and exported to the cytosol through SLC25A1 (also known as citrate
spermine) to facilitate their secretion from cells and in fine their carrier), followed by the regeneration of oxaloacetate and acetyl-
excretion with urine (Pegg, 2008). This pathway may be impor- CoA upon the ATP- and CoA-dependent reaction catalyzed by
tant for increasing energy expenditure upon inhibition of nicotin- ACLY (Zaidi et al., 2012). Cytosolic oxaloacetate is the substrate
amide N-methyltransferase (NNMT) in adipocytes (Kraus et al., of malate dehydrogenase 1, NAD (soluble) (MDH1), catalyzing
2014). Extramitochondrial variants of the acetyl-CoA thiolase the NADH-dependent synthesis of malate, which can be trans-
complex and HMGCS (i.e., HMGCS1) employ three acetyl- ported back to the mitochondrial matrix via solute carrier family
CoA molecules to synthesize 3-hydroxy-3-methyglutaryl-CoA 25 (mitochondrial carrier; dicarboxylate transporter), member 10
(HMGC) (Edwards and Ericsson, 1999). Whereas mitochondrial (SLC25A10), an inorganic phosphate/dicarboxylate antiporter
HMGC generally feeds the synthesis of ketone bodies, its cyto- (Mizuarai et al., 2005), or solute carrier family 25 (mitochondrial
solic counterpart is metabolized by 3-hydroxy-3-methyl-glu- carrier; oxoglutarate carrier), member 11 (SLC25A11), an a-keto-
taryl-CoA reductase (HMGCR, the pharmacological target of glutarate/malate antiporter (Wallace, 2012). Alternatively, malic
statins) within the mevalonate pathway, which is essential in all enzyme 1, NADP(+)-dependent, cytosolic (ME1) can convert
cells for the production of sterols, ubiquinone (coenzyme Q10), malate into pyruvate, which can re-enter the mitochondrial
heme A, and other isoprenoids (Edwards and Ericsson, 1999). matrix via the MPC (Bender et al., 2015). Acetyl-CoA is also ex-
Finally, cytosolic acetyl-CoA is required for cell type-specific ported from mitochondria via the carnitine shuttle. As mentioned
metabolic circuitries, such as the synthesis of acetylcholine, above, fatty acids enter mitochondria in the form of acylcarnitine
implying that the survival and activity of cholinergic neurons via the antiporter SLC25A20, which generally exchanges them
are particularly dependent on acetyl-CoA (Szutowicz et al., with free L-carnitine (Rebouche and Seim, 1998). Mitochondrial
2013). L-carnitine can also be converted by carnitine O-acetyltransfer-
Peroxisomal Metabolism of Acetyl-CoA in Yeast ase (CRAT) into acetyl-L-carnitine, and the latter shares with free
The peroxisomal metabolism of acetyl-CoA has not been studied L-carnitine the ability to drive the SLC25A20 antiporter. Finally,
in detail in the mammalian system (Chen et al., 2012). In yeast, cytosolic acetyl-L-carnitine can regenerate acetyl-CoA and
b-oxidation underlies the synthesis of a significant fraction of L-carnitine via the CoA-dependent reaction catalyzed by a
the peroxisomal acetyl-CoA pool (Choudhary et al., 2014). In cytosolic variant of CRAT (Madiraju et al., 2009). Thus, the cit-
addition, yeast cells can produce acetyl-CoA within peroxi- rate-malate-pyruvate and the carnitine shuttle may ensure the
somes directly from acetate, a CoA-dependent reaction cata- continuous transfer of acetyl-CoA from mitochondria to the
lyzed by acetate-CoA ligase 1 (Acs1) (Chen et al., 2012). Finally, cytosol. Of note, the enzymatic activity of CRAT in skeletal mus-
yeast cells employ the majority of peroxisomal acetyl-CoA to cles appears to be critical for whole-body glucose tolerance and
feed the glyoxylate cycle, a metabolic circuitry that generates metabolic fitness (Muoio et al., 2012). Most likely, this reflects the
succinate for carbohydrate synthesis (Kunze et al., 2006). Of ability of CRAT to drive the export of excess acetyl-CoA from the
note, recent data suggest that (at least some) human tissues mitochondrial matrix, hence preventing PDC substrate inhibition
may be endowed with enzymatic activities that are required (Muoio et al., 2012). Taken together with the data obtained with
for the glyoxylate cycle, such as the ability to reversibly convert muscle-specific Mlycd–/– mice (Koves et al., 2008), these obser-
acetyl-CoA, glyoxylate, and H2O into malate and CoA (Strittmat- vations connect insulin (INS) resistance with a situation of mito-
ter et al., 2014). Nonetheless, the glyoxylate cycle is still consid- chondrial overload characterized by excess b-oxidation and high
ered as an anabolic pathway operating in lower organisms only. acetyl-CoA levels.
The acetyl-CoA concentration gradient across the inner
Compartmentalization of Acetyl-CoA Metabolism mitochondrial membrane is influenced not only by the rate of
Acetyl-CoA exists in separate mitochondrial, peroxisomal, acetyl-CoA synthesis and consumption in the cytosol and within
nucleo-cytosolic, and intrareticular pools (Figure 2). Indeed, the mitochondria, but also by the activity of: (1) the citrate carrier
inner mitochondrial, peroxisomal, and reticular membranes (SLC25A1), which can be increased by pro-inflammatory tran-
are impermeant to the highly charged acetyl-CoA molecule. scription factors like NF-kB and signal transducer and activator

Cell Metabolism
Review
Figure 2. Compartmentalization of Acetyl-CoA Metabolism

The subcellular fluxes of acetyl coenzyme A (acetyl-CoA) are tightly regulated. Two multicomponent systems ensure the exchange of acetyl-CoA between the
nucleo-cytosolic compartment and mitochondria: the so-called ‘‘carnitine shuttle’’ and the so-called ‘‘citrate-malate-pyruvate shuttle.’’ The former plays a key
role in b-oxidation and branched-chain amino acid (BCAA) mitochondrial catabolism, as it allows cytosolic acyl-CoA (derived from free fatty acids, FFAs) and
a-ketoacids (derived from BCAAs) to enter the mitochondrial matrix upon conjugation with L-carnitine. The actual import of these species into mitochondria is
coupled to the export of L-carnitine or acetyl-L-carnitine, and acetyl-L-carnitine can be metabolized by a cytosolic variant of carnitine O-acetyltransferase (CRAT)
to generate acetyl-CoA (and free L-carnitine). The latter allows for the exchange of several metabolic intermediates between the cytosol and mitochondria,
including citrate, oxaloacetate, a-ketoglutarate, glutamate, and aspartate. In doing so, the citrate-malate-pyruvate shuttle provides substrates for anabolic
metabolism (in energy-high conditions) or supports bioenergetic metabolism (in energy-low conditions). AT1 (official name SLC33A1) is responsible for the import
of acetyl-CoA into the endoplasmic reticulum (ER) lumen. a-KG, a-ketoglutarate; ACLY, ATP citrate lyase; AGC, aspartate/glutamate carrier (SLC25A13); Asp,
aspartate; CACT, carnitine/acylcarnitine translocase (SLC25A20); Cit, citrate; CS, citrate synthase; CTP, citrate transporter (SLC25A1); DIC, dicarboxylate carrier
(SLC25A10); Glu, glutamate; GLUD1, glutamate dehydrogenase 1; GLUD2, glutamate dehydrogenase 2; GOT1, glutamic-oxaloacetic transaminase 1, soluble;
GOT2, glutamic-oxaloacetic transaminase 2, mitochondrial; Mal, malate; MDH1, malate dehydrogenase 1, NAD (soluble); MDH2, malate dehydrogenase 2, NAD
(mitochondrial); ME1, malic enzyme 1, NADP(+)-dependent, cytosolic; MPC1, mitochondrial pyruvate carrier 1; MPC2, mitochondrial pyruvate carrier 2; OAA,
oxaloacetate; OGC, oxoglutarate carrier (SLC25A11); PDC, pyruvate decarboxylase; Pi, inorganic phosphate; Pyr, pyruvate.
of transcription 1 (STAT1) (Infantino et al., 2014); and (2) ACLY, Export of Acetyl-CoA from Peroxisomes
which is regulated by several signal transducers, including Kirs- In yeast cells, peroxisomal acetyl-CoA can be exported to the
ten rat sarcoma viral oncogene homolog (KRAS) and v-akt nucleo-cytosolic compartment by at least two distinct mecha-
murine thymoma viral oncogene homolog 1 (AKT1) (Berwick nisms: (1) via a carnitine shuttle, relying on the generation of
et al., 2002; Lee et al., 2014). Of note, the export of citrate from peroxisomal acetyl-L-carnitine by the yeast ortholog of CRAT
mitochondria creates the need for the anaplerotic replenishment (Franken et al., 2008); and (2) in the form of succinate, one of
of TCA cycle intermediates that regenerate oxaloacetate, mean- the products of the glyoxylate cycle (which consumes acetyl-
ing that the extracellular availability of glutamine and the CoA) (Kunze et al., 2006). Of note, the release of succinate
metabolic flux through glutaminolysis also influence the relative does entail a reduction in peroxisomal pool acetyl-CoA, but not
abundance of mitochondrial and cytosolic acetyl-CoA (Yang a direct increase in its nucleo-cytosolic counterpart.
et al., 2014). Finally, acetyl-CoA might be non-specifically Import of Acetyl-CoA into the Endoplasmic Reticulum
released from the mitochondrial matrix upon transient openings The transfer of acetyl-CoA from the cytosol to the ER lumen is
of the so-called ‘‘permeability transition pore complex,’’ a multi- mediated by solute carrier family 33, member 1 (SLC33A1, also
component channel built across the inner and outer mitochon- known as AT1) (Kanamori et al., 1997), a protein that is mutated
drial membranes permeant to solutes < 1.5 kDa and involved in spastic paraplegia 42, an autosomal dominant neurodegener-
in the regulation of cell death (Galluzzi et al., 2015a). This ative disease characterized by muscle wasting and progressive
possible mechanism of acetyl-CoA release has not been investi- weakness of the inferior limbs (Lin et al., 2008). Importantly,
gated in detail thus far. SLC33A1 is transactivated by X-box binding protein 1 (XBP1),

Cell Metabolism
Review
an ER stress-responsive factor (Damiano et al., 2015). Thus, CoA levels fall well before the concentration of ATP and NADH
reticular acetyl-CoA levels are expected to increase (at the diminishes. Such a drop is more pronounced in the cytosolic
expense of the nucleo-cytosolic pool) in the course of ER stress fraction than in whole-cell extracts, suggesting (but not demon-
responses (Galluzzi et al., 2014). In the ER lumen, acetyl-CoA is strating unequivocally) that the mitochondrial pool of acetyl-CoA
the substrate of a few acetyltransferases including members of is less susceptible to variations than it nucleo-cytosolic counter-
the N-acetyltransferase 8 (NAT8) protein family and calreticulin part (Mariño et al., 2014). The reduction in intracellular acetyl-
(CALR, a chaperone with acetyltransferase enzymatic activity) CoA levels can be detected as early as 30 min after the
(Ding et al., 2014). Acetylation reactions in the ER lumen may switch of culture conditions and can be avoided by providing
allow correctly folded proteins to progress to the Golgi appa- various acetyl-CoA precursors, including dimethyl-a-ketogluta-
ratus for secretion, implying that the reticular pool of acetyl- rate (a cell-permeant form of a-ketoglutarate), leucine or its de-
CoA could play an important role in protein quality control (Pehar rivative a-ketoisocaproic acid, pyruvate, and PDC stimulators
and Puglielli, 2013). Interestingly, N-acetyltransferase 8-like (like lipoic acid and DCA) (Mariño et al., 2014). Conversely,
(NAT8L) is specifically expressed by neurons, where it plays a when cancer cells are cultured in rich media, various selective
key role as it catalyzes the synthesis of N-acetylaspartate, the manipulations of acetyl-CoA metabolism effectively can reduce
most prominent storage and transport form of acetyl groups in intracellular acetyl-CoA levels. These interventions include the
the brain (Moffett et al., 2013). pharmacological or genetic inhibition of the MPC heterodimer,
Compartmentalized Regulation of Protein Acetylation CPT1, the BCKD complex, the citrate carrier (SLC25A1),
The compartmentalization of acetyl-CoA pools has a major ACLY, and ACSS2 (Mariño et al., 2014). Thus, all these pathways
impact on protein acetylation, be it non-enzymatic or be it cata- appear to contribute to the maintenance of optimal acetyl-CoA
lyzed by NATs or KATs. The rate of non-enzymatic acetylation, levels, at least in human malignant cells cultured in standard
which presumably relies on the highly reactive intermediate conditions.
acetyl-phosphate (functioning as the donor of acetyl groups), is Also, oncogenes may affect acetyl-CoA concentrations. The
strongly influenced by the physicochemical properties of the overexpression of the anti-apoptotic protein BCL2-like 1
microenvironment (Kuhn et al., 2014). This implies that intracel- (BCL2L1, best known as BCL-XL) appears to reduce the
lular pH gradients, such as the one built across the inner mito- amounts of citrate, acetyl-CoA, and Na-acetylated proteins in
chondrial membrane by respiratory chain complexes I–IV, may the cytoplasm, and this would etiologically contribute to onco-
influence acetylation reactions (Wagner and Payne, 2013). More- genesis (Yi et al., 2011). To the best of our knowledge, however,
over, spermidine can compete with acetyl-CoA for binding to this report has not been confirmed by independent investigators
EP300 (and perhaps other acetyltransferases), hence increasing yet. The knockout of Myc in rat fibroblasts results in decreased
the acetyl-CoA concentration required for optimal acetyltrans- acetyl-CoA levels (Edmunds et al., 2014), corroborating the
ferase activity (Pietrocola et al., 2015). Since spermidine levels notion that Myc family members normally stimulate mitochon-
vary in different organelles (Casero and Marton, 2007), this phe- drial acetyl-CoA production (and histone acetylation) (Morrish
nomenon may contribute to the compartmentalized regulation of et al., 2010). Similar observations (i.e., increased acetyl-CoA/
protein acetylation. Specific acetyltransferases and deacety- CoA ratio and/or histone acetylation levels) have been made:
lases are also subjected to subcellular compartmentalization. (1) upon the transgenic expression of a myristoylated, constitu-
This applies, for instance, to EP300 as well as to the deacetylase tively active variant of AKT1 (myrAKT1) in cultured human glio-
SIRT1, both of which shuttle between the nucleus and the blastoma cells; (2) upon the constitutive expression of oncogenic
cytosol (Chang and Guarente, 2014). Another deacetylase of KRAS, stimulating accrued AKT1 signaling, in pancreatic cells
the sirtuin family, i.e., SIRT3, localizes for the most part to the in vivo; as well as (3) following the doxycycline-inducible expres-
mitochondrial matrix, and its expression levels have been corre- sion of myrAKT1 in mammary epithelial cells in vivo (Lee et al.,
lated with differential patterns of mitochondrial protein acetyla- 2014). At least in part, the ability of AKT1 to promote the accumu-
tion both in baseline conditions (Dittenhafer-Reed et al., 2015) lation of acetyl-CoA originates from its ability to phosphorylate
and in the course of chronic caloric restriction (Hebert et al., ACLY on S455, hence stimulating its catalytic activity (Lee
2013). Importantly, the deacetylase activity of sirtuins obligatorily et al., 2014). These data lend further support to the notion that
relies on NAD+ as a cofactor, establishing yet another link be- increased levels of acetyl-CoA and acetylated histones may be
tween metabolism and protein acetylation levels. required to sustain the accelerated proliferation of cancer cells.
Changing Acetyl-CoA Levels In Vivo
Fluctuations of Acetyl-CoA Levels Mice deprived of food (but with access to water ad libitum) for
At odds with ATP levels, which are relatively stable (to support 24 hr exhibit a significant reduction in total acetyl-CoA levels in
bioenergetic homeostasis), the abundance of acetyl-CoA fluctu- several organs, including the heart and muscles, corresponding
ates in response to both intracellular and extracellular cues. Thus, to a decrease in protein acetylation levels (Mariño et al., 2014).
acetyl-CoA levels have been shown to vary even in the course of However, the same experimental conditions have no major
embryonic development (Tsuchiya et al., 2014). Unfortunately, effects on acetyl-CoA concentrations in the brain (Mariño
however, acetyl-CoA is generally quantified in whole-cell or et al., 2014) and actually increase hepatic acetyl-CoA and
whole-organ extracts, and very few studies have measured protein acetylation levels (Chow et al., 2014). This latter phenom-
changing acetyl-CoA concentrations at the subcellular level. enon has been causally linked to the mobilization of subcutane-
Changing Acetyl-CoA levels in Cultured Cells ous fat stores, one of the first effects of short-term fasting
When human cancer cells are switched from normal culture me- (Browning et al., 2012). In fasting conditions, indeed, fatty acids
dia to serum- and nutrient-free conditions, intracellular acetyl- are released by adipocytes and employed (at least in part) as

Cell Metabolism
Review
substrate for b-oxidation (which produces acetyl-CoA) within he- elevate mitochondrial acetyl-CoA levels, ultimately promoting
patocytes (which are particularly rich in mitochondria) (Browning hepatic gluconeogenesis by virtue of its capacity to allosterically
et al., 2012). Repeated intraperitoneal injections of dimethyl- activate PC and inhibit the PDC. Further supporting this notion,
a-ketoglutarate or dichloroacetate (DCA) efficiently prevent the mice genetically endowed with a muscle-specific defect in
drop of acetyl-CoA levels provoked by starvation in the heart b-oxidation are significantly less prone to develop diet-induced
and muscle of mice (Mariño et al., 2014). Along similar lines, INS resistance than their wild-type counterparts (see above)
the provision of excess acetate has been shown to increase (Koves et al., 2008).
acetyl-CoA levels in the hypothalamus upon the activation of
ACAC, eventually resulting in the synthesis of anorectic neuro- Acetyl-CoA and Gene Expression
peptides and appetite suppression (Frost et al., 2014). Finally, In multiple cell types, histone acetylation is highly sensitive to the
ethanol intake augments acetyl-CoA levels in hepatic mitochon- availability of acetyl-CoA (Cai et al., 2011; Donohoe et al., 2012;
dria (Fritz et al., 2013). Lee et al., 2014; Moussaieff et al., 2015; Takahashi et al., 2006;
The aforementioned findings indicate that alterations in food Wellen et al., 2009). Acetyl-CoA is indeed the obligate cofactor
and alcohol intake have a direct impact on intracellular acetyl- for histone acetyltransferases (HATs), meaning that the abun-
CoA levels. However, it appears unlikely that the starvation- dance of the nucleo-cytosolic pool may have a direct impact
induced decrease of acetyl-CoA in the heart and muscles solely on the enzymatic activity of HATs, especially those with a rela-
and directly results from reduced glucose availability. Indeed, tively high KD for acetyl-CoA. Thus, drops in nucleo-cytosolic
intracellular acetyl-CoA concentrations drop well before glyce- acetyl-CoA levels below the KD of specific HATs may directly
mia decreases, at the same time as circulating triglycerides in- reduce their activity. Moreover, several HATs including GCN5
crease. This phenomenon may therefore reflect the ability of are subjected to product inhibition by free CoA (Tanner et al.,
starvation to cause a diminution in the plasma levels of various 2000). This indicates that the acetyl-CoA/CoA ratio may be the
cytokines and growth factors, including INS and insulin-like relevant regulator of the enzymatic activity of HATs, rather than
growth factor 1 (IGF1), coupled to an increase in the circulating the absolute levels of acetyl-CoA (Lee et al., 2013). Irrespective
amounts of the IGF1 antagonist insulin-like growth factor binding of the underlying mechanisms, this establishes a direct link be-
protein 1 (IGFBP1) (Cheng et al., 2014). Limited growth factor tween the nucleo-cytosolic abundance of acetyl-CoA and the
signaling results indeed in reduced AKT1 activation, which has epigenetic control of gene expression. Indeed, high levels of his-
(at least) two negative consequences for acetyl-CoA meta- tone acetylation are required not only to support global tran-
bolism. First, AKT1 signaling is required for normal glucose up- scription (Moussaieff et al., 2015; Takahashi et al., 2006), but
take through plasma membrane glucose transporters (Wieman also for the preferential transactivation of genes involved in cell
et al., 2007). Second, AKT1 normally phosphorylates ACLY on growth and replication (Cai et al., 2011; Donohoe et al., 2012;
S455, hence stimulating acetyl-CoA production (Lee et al., Lee et al., 2014; Shi and Tu, 2013), glycolysis (Wellen et al.,
2014). Although this hypothetical pathway linking starvation to 2009), and resistance to oxidative stress (Shimazu et al., 2013).
dwindling acetyl-CoA levels has not been formally explored Fluctuations in metabolites other than acetyl-CoA also affect
in vivo, signs of AKT1 activation (i.e., AKT1 phosphorylation on histone acetylation, hence impacting transcription both quantita-
S473) positively correlate with histone acetylation levels in hu- tively and qualitatively. Besides feeding the TCA (and hence
man gliomas and prostate cancers (Lee et al., 2014). Another stimulating the synthesis of acetyl-CoA) (Donohoe et al., 2012),
major pathway that may link starvation to dropping acetyl-CoA D-b-hydroxybutyrate inhibits HDAC1, HDAC2, and HDAC3 (Shi-
levels in some cells involves SIRT1, which is activated in en- mazu et al., 2013). Along similar lines, L-carnitine and sphingo-
ergy-low conditions (high NAD+ levels) (Morselli et al., 2010) sine-1-phosphate favor histone acetylation by operating as
and inhibits ACSS2 (Sahar et al., 2014). This latter effect may HDAC1 and HDAC2 inhibitors (Hait et al., 2009; Huang et al.,
explain the circadian rhythmicity of hepatic acetyl-CoA levels 2012). Conversely, increases in the NAD+/NADH ratio (which
in mice (Sahar et al., 2014). Finally, some tissues may experience accompany starvation) promote histone deacetylation by stimu-
intracellular acetyl-CoA depletion in response to organismal lating the activity of sirtuins (Guarente, 2013). Also variations in
starvation as a consequence of limited glutamine availability, at intracellular pH (pHi) have a major impact on histone acetylation.
least hypothetically (Pozefsky et al., 1976). This possibility awaits Intracellular acidification (i.e., decreased pHi) promotes the ac-
experimental verification. Irrespective of this open issue, it tivity of histone deacetylases (as well as the export of protonated
seems likely that several mechanisms operating in parallel con- acetate via monocarboxylate transporter as a pHi buffer mecha-
nect organismal starvation with the decrease in intracellular nism), whereas intracellular alkalinization (i.e., increased pHi)
acetyl-CoA levels observed in some tissues. augments global histone acetylation (McBrian et al., 2013).
Obviously, metabolic disorders also affect acetyl-CoA con- Thus, histone acetylation appears to function as a rheostat to
centrations. For example, type 1 diabetes causes a major in- regulate pHi. Of note, the chromatin of mammalian cells contains
crease in hepatic acetyl-CoA concentrations (Perry et al., at least 109 potential acetylation sites, meaning that massive his-
2014). Interestingly, this effect can be mimicked by a 3-day tone acetylation may cause a sizeable depletion of the nucleo-
high-fat dietary regimen combined with an artificial elevation of cytosolic acetyl-CoA pool, hence impacting cellular metabolism.
circulating corticosterone levels (which occur spontaneously in Conversely, the acetyl residues stored in histones may be mobi-
animal models of type 1 diabetes) and can be reverted by the lized to generate acetate as an energy source (Martinez-Pastor
administration of mifepristone, an antagonist of glucocorticoid et al., 2013). All these examples underscore the intricate links be-
receptors (Perry et al., 2014). Thus, the increased turnover of tween metabolism and histone acetylation levels, which in turn
fatty acids and acetate associated with type I diabetes may influence gene expression both quantitatively and qualitatively.

Cell Metabolism
Review
Figure 3. Impact of the Acetyl-CoA/CoA Ratio on Global Cellular Functions

The relative abundance of acetyl coenzyme A (acetyl-CoA) and coenzyme A (CoA) controls various cellular processes, including cell growth and mitosis,
regulated cell death (RCD), and autophagy. For instance, elevated acylation levels of histones, transcription factors (TFs), and various enzymes have been
associated with intensive growth and proliferation. The pro-apoptotic activity of caspase-2 (CASP2), which appears to require Na-acetylation, is controlled upon
physical sequestration by 14-3-3z, and this inhibitory interaction is promoted by the calcium/calmodulin-dependent protein kinase II (CAMK2)-dependent
phosphorylation of CASP2 as well as by the sirtuin 1 (SIRT1)-dependent deacetylation of 14-3-3z (two processes that are favored by low acetyl-CoA/CoA ratios).
Finally, the accumulation of CoA at the expense of acetyl-CoA favors the SIRT1- and E1A binding protein p300 (EP300)-dependent deacetylation of various ATG
proteins, promotes the activation of AMPK, and inhibits v-akt murine thymoma viral oncogene homolog 1 (AKT1) signaling, globally stimulating the autophagic
flux. HAT, histone acetyltransferase; KAT, lysine acetyltransferase; MTORCI, mechanistic target of rapamycin complex I; NAT, Na acetyltransferase; ULK1, unc-
51-like autophagy activating kinase 1.
Fluctuations in the nucleo-cytosolic pool of acetyl-CoA also the enzymatic activity of CBP responds to physiological varia-
modulate gene expression by altering the acetylation state of tions in acetyl-CoA levels, at least in some cell types (Xu et al.,
transcription factors. Thus, acetate stimulates erythropoiesis in 2014). It has not yet been demonstrated whether this holds
multiple mouse models of anemia by activating a signaling true for other KATs operating on transcription factors. In spite
pathway that involves (1) the conversion of acetate into acetyl- of this uncertainty, these examples illustrate the broad effects
CoA (by ACSS2); (2) the acetylation of endothelial PAS domain of (de)acetylation reactions on the control of gene expression.
protein 1 (EPAS1) by CBP; and (3) the recruitment of a transcrip-
tionally active EPAS1-containing complex to the promoter of the Acetyl-CoA and Cellular Anabolism versus Catabolism
gene encoding erythropoietin (Xu et al., 2014). Other prominent Increased nucleo-cytosolic acetyl-CoA levels shift cellular meta-
transcription factors that are regulated by CBP- or EP300- bolism toward anabolic reactions as they shut off catabolic cir-
dependent acetylation as well as by SIRT1- or HDAC1-mediated cuitries. This effect is not limited to basic biochemical circuitries,
deacetylation are forkhead box O (FOXO) proteins (van der Horst but involves complex cellular (and organismal) programs. Thus,
and Burgering, 2007) and tumor protein p53 (TP53) (Xu, 2003). acetyl-CoA levels affect the propensity of cells to grow, progress
FOXO1 plays an important role in linking caloric restriction to life- along the cell cycle, mount autophagic responses to stress, and
span extension in several model organisms (Kim et al., 2015). succumb to RCD (Figure 3). In addition, the abundance of acetyl-
TP53 is a key regulator of homeostasis in physiological and path- CoA in defined cell types influences the metabolic relationship
ological conditions, and its activity is controlled by several post- between different organs, as well as behavioral cues such as
translational modifications, including acetylation at multiple (at appetite control.
least seven) lysine residues (Tang et al., 2008). Besides EP300 Cell Growth and Mitosis
and CBP, at least four other KATs can acetylate TP53, namely, By favoring histone acetylation, elevated acetyl-CoA levels stim-
KAT2B (also known as PCAF), KAT6A (also known as MOZ), ulate the expression of multiple genes that are required for cell
KAT5 (also known as TIP60), and KAT8 (also known as MOF). growth and proliferation (Cai et al., 2011; Donohoe et al., 2012;
Acetylation opens the conformation of TP53, alters its ability to Lee et al., 2014; Shi and Tu, 2013; Wellen et al., 2009). In yeast,
bind specific response elements on DNA, and generally in- the Acs1-dependent synthesis of acetyl-CoA does not only sup-
creases its transcriptional activity (Tang et al., 2008). Of note, port global transcription, but it also allows for the preferential

Cell Metabolism
Review
transactivation of various genes involved in cell growth and repli- by SIRT1 in the nucleus, allowing it to shuttle back to the cyto-
cation, like those encoding cyclin CLN3, several ribosomal sub- plasm (in complex with tumor protein p53 inducible nuclear
units, and glycolytic enzymes (Cai et al., 2011; Shi and Tu, 2013). protein 2, TP53INP2) and participate in the assembly of autopha-
In contrast, when yeast cells enter the stationary phase during gosomes (Huang et al., 2015). ATG9A, a protein that shuttles
the so-called ‘‘diauxic shift’’ (i.e., the transition of cultured yeast between the juxta-nuclear trans-Golgi compartment and late en-
from a fermentative to a respiratory metabolism), acetyl-CoA dosomes, must also be deacetylated for autophagy to proceed
levels and global histone acetylation decrease. In this context, normally (Pehar et al., 2012). In line with this notion, loss-of-func-
a minority of so-called histone hypoacetylation-activated genes tion mutations of SLC33A1, resulting in a depletion of reticular
(which are repressed during the exponential growth phase) acetyl-CoA, cause excessive autophagy (Peng et al., 2014).
become activated (Mehrotra et al., 2014). In the mammalian sys- The knockdown of biogenesis of lysosomal organelle com-
tem, high acetyl-CoA concentrations also favor cell growth and plex-1, subunit 1 (BLOC1S1, a mitochondrial KAT also known
replication at the expenses of differentiation (Moussaieff et al., as GCN5L1) favors the deacetylation of mitochondrial proteins
2015; Shan et al., 2014; Sutendra et al., 2014). Embryonic while stimulating mitophagy (Webster et al., 2013), an organ-
stem cells quickly lose pluripotency along with a metabolic shift elle-specific type of autophagy targeting mitochondria (Green
involving decreased glycolytic activity, lowered acetyl-CoA et al., 2011). Beyond putative direct effects on mitochondria,
availability, and histone deacetylation (Moussaieff et al., 2015). BLOC1S1 may control the activity of the pro-autophagic tran-
In line with this notion, artificially preserving acetyl-CoA levels scription factor EB (TFEB) (Pietrocola et al., 2013). Bloc1s1 /
though the exogenous supply of acetate efficiently delays mouse embryonic fibroblasts indeed exhibit increased expres-
embryonic stem cell differentiation as it preserves histone acet- sion levels of TFEB and its downstream targets (Scott et al.,
ylation (Moussaieff et al., 2015). Cancer cells, which are charac- 2014), providing yet another link between deacetylation and
terized by increased proliferation rates, ectopically synthesize the activation of a pro-autophagic transcriptional program.
acetyl-CoA in the nucleus (perhaps in an S phase-specific These examples illustrate how the depletion of acetyl-CoA in
manner), resulting in increased histone acetylation levels distinct subcellular compartments can ignite autophagy via a
(Comerford et al., 2014; Sutendra et al., 2014; Takahashi et al., multipronged effect on various autophagy-regulatory processes.
2006; Wellen et al., 2009). Transcriptomic studies revealed that Several inducers of autophagy, including (but not limited to)
a significant proportion of the genes that are responsive to caloric restriction and spermidine, have lifespan-extending
acetyl-CoA (and hence histone acetylation) levels are involved effects in various model organisms, including yeast, worms, flies,
in DNA replication, cell cycle progression, and general anabo- and mice (Madeo et al., 2014), as they lower global protein acet-
lism (Lee et al., 2014). Of note, the acetylation of phosphogluco- ylation levels (Mariño et al., 2014). Intriguingly, reduced levels of
nate dehydrogenase (PDG) by a cytosolic variant of DLAT and Myc also increase the lifespan of flies (Greer et al., 2013) and
acetyl-CoA acetyltransferase 2 (ACAT2) augments its enzymatic mice (Hofmann et al., 2015) and are associated with lowered
activity, hence promoting cellular anabolism as a consequence nucleo-cytosolic acetyl-CoA levels (Edmunds et al., 2014; Mor-
of an increased metabolic flux through the pentose phosphate rish et al., 2010). Along similar lines, nucleo-cytosolic acetyl-
pathway (PPP) (Shan et al., 2014). Altogether, these ob- CoA metabolism has been genetically linked to autophagy
servations suggest that increased acetyl-CoA concentrations regulation and lifespan in yeast and Drosophila melanogaster
promote cell growth and replication via transcriptional and (Eisenberg et al., 2014). Yeast cells overexpressing the ortholog
non-transcriptional mechanisms. of mammalian ACSS2 (i.e., Acs2p) indeed exhibit reduced
Catabolism and Autophagy lifespan as compared to their wild-type counterparts. Moreover,
The depletion of nucleo-cytosolic acetyl-CoA activates AMPK the brain-specific knockout of AcCoAS (the sole ortholog
and inhibits the mechanistic target of rapamycin (MTOR) com- of mammalian ACSS1 and ACSS2 in Drosophila) suffices
plex I (MTORCI), hence arresting anabolic reactions and stimu- to extend fly lifespan (Eisenberg et al., 2014). It has not been
lating autophagy (Galluzzi et al., 2015b; Mariño et al., 2014). tested yet whether direct genetic manipulations of acetyl-CoA
Histone deacetylation caused by the shortage of acetyl-CoA metabolism may have lifespan-extending effects in mammals
favors the expression of pro-autophagic genes (Eisenberg as well. Moreover, it remains to be determined whether the
et al., 2014), whereas cytoplasmic deacetylation reactions acti- autophagy-inducing and antidiabetic effects of endurance
vate various proteins that are required for autophagy (Mariño training (He et al., 2012) may be ultimately linked to decreased
et al., 2014). In line with this notion, replenishing the nucleo-cyto- mitochondrial protein acetylation levels, as it is the case for
solic pool of acetyl-CoA by the microinjection of acetyl-CoA into rats selectively bred for a high running capacity (Overmyer
cultured human cells or by the systemic administration of diet al., 2015).
methlyl-a-ketoglutarate to mice suppresses starvation-induced Regulated Cell Death
autophagy (Mariño et al., 2014). In human cells, low acetyl- The acetyl-CoA/CoA ratio appears to influence the propensity
CoA levels restrain the enzymatic activity of EP300, and epistatic of cells to undergo regulated variants of cell death, including
analyses suggest that the inhibition of EP300 is largely respon- caspase-dependent apoptosis and regulated necrosis (Green
sible for autophagy induction in these conditions (Mariño et al., et al., 2014). To mention one example, the acetyl-CoA/CoA ratio
2014). Various proteins of the autophagic machinery, including appears to be involved in a complex system of regulation of
ATG5, ATG7, and ATG12, are acetylated (and hence inhibited) caspase-2 (CASP2), an apoptotic protease. CoA (but less so
by EP300 or deacetylated (and hence activated) by SIRT1 acetyl-CoA) interacts with calcium/calmodulin-dependent pro-
(Madeo et al., 2014) Moreover, microtubule-associated protein tein kinase II (CAMK2), hence reducing its threshold for activa-
1 light chain 3 (MAP1LC3, best known as LC3) is deacetylated tion by Ca2+ ions (McCoy et al., 2013). Active CAMK2 can

Cell Metabolism
Review
(legend on next page)

Cell Metabolism
Review
Table 1. Main Pharmacological Modulators of Acetyl-CoA Metabolism

Family Molecule Indication(s) Development Status References
ACAC inhibitors TOFA Metabolic disorders Preclinical Harwood, 2005
ACLY inhibitors BMS-303141 Cancer Preclinical Hatzivassiliou et al., 2005;
Hydroxycitrate Cancer, obesity Phase IV clinical development Madeo et al., 2014
SB-204990 Cancer Preclinical
ACSS2 inhibitors 1-(2,3-di(thiophen-2-yl)quinoxalin- Cancer Preclinical Comerford et al., 2014;
6-yl)-3-(2-methoxyethyl)urea Mashimo et al., 2014
CPT1 inhibitors Etomoxir Cardiac disorders Terminated Abozguia et al., 2006
Perhexiline Cardiac disorders Phase II clinical development
Trimetazidine Cardiac disorders Phase IV clinical development
CRAT inhibitors Mildronate Cardiac disorders Approved Makrecka et al., 2014
GLS inhibitors BC-839 Cancer Preclinical Durán et al., 2012
DON Cancer Preclinical
HDAC inhibitors Belinostat Cancer Phase II clinical development Falkenberg and Johnstone,
Parabinostat Cancer Phase III clinical development 2014
Romidepsin Cancer Approved
Valproic acid Cancer Phase III clinical development
Vorinostat Cancer Approved
HMGCR inhibitors Statins Cancer, metabolic Approved Brautbar and Ballantyne,
disorders 2011; Demierre et al., 2005
KAT inhibitors Anacardic acid Cancer Preclinical Harwood, 2005
C646 Cancer Preclinical
Curcumin Cancer, metabolic Phase II clinical development
disorders
Garcinol Cancer Preclinical
MB-3 Cancer Preclinical
MPC inhibitors UK5099 Cancer Preclinical Mariño et al., 2014
PDC activators DCA Cancer Approved (for lactic acidosis) Galluzzi et al., 2013
Metabolic disorders
PDC inhibitors CPI-613 Cancer Phase II clinical development Pardee et al., 2014
SIRT1 activators Resveratrol Aging, cancer, Phase III clinical development Athar et al., 2007; Baur
metabolic disorders and Sinclair, 2006
SRT1720 Aging, metabolic Preclinical
disorders
SLC25A1 inhibitors 1,2,3-BTC Cancer Preclinical Aluvila et al., 2010
1,2,3-BTC, 1,2,3-benzenetricarboxylate; ACAC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ACSS2, acyl-CoA synthetase short-chain family
member 2; CPT1, carnitine palmitoyltransferase 1; CRAT, carnitine O-acetyltransferase; DON, 6-diazo-5-oxo-L-norleucine; GLS, glutaminase;
HDAC, histone deacetylase; HMGCR, 3-hydroxy-3-methyl-glutaryl-CoA reductase; KAT, lysine acetyl transferase; MPC, mitochondrial pyruvate car-
rier; PDC, pyruvate dehydrogenase complex; SIRT1, sirtuin 1; TOFA, 5-(tetradecyloxy)-2-furoic acid).
phosphorylate CASP2, which favors the inhibitory interaction of et al., 2011), which is supported by high acetyl-CoA levels.
the latter with tyrosine 3-monooxygenase/tryptophan 5-mono- Thus, a decreased acetyl-CoA/CoA ratio would promote cell
oxygenase activation protein, zeta (YWHAZ, best known as survival by multiple mechanisms impinging on the activity of
14-3-3z) (Nutt et al., 2009). Moreover, SIRT1 can promote the CASP2. Of note, the phosphorylation of CASP2 by CAMK2 re-
anti-apoptotic functions of 14-3-3z by deacetylating it, a reaction quires NADPH, a key antioxidant (and co-enzymatic reducing
that is also favored by the accumulation of CoA at the expenses agent) mainly generated by the PPP (Galluzzi et al., 2013).
of acetyl-CoA (Andersen et al., 2011). Finally, the full-blown Hence, oxidative stress can stimulate cell death by releasing
apoptotic activity of CASP2 may rely on Na-acetylation (Yi CASP2 from inhibition by 14-3-3z (Nutt et al., 2009). Apparently
Figure 4. Expression Levels of Proteins Involved in Acetyl-CoA Metabolism

(A and B) The expression levels of proteins that participate in acetyl coenzyme A (acetyl-CoA) metabolism in the indicated cell types were retrieved
from The Human Protein Atlas (http://www.proteinatlas.org/). Proteins were arbitrarily subdivided according to function in ‘‘metabolic enzymes’’ (A)
and ‘‘transporters,’’ ‘‘acetyltransferases,’’ and ‘‘deacetylases’’ (B) and subjected to hierarchical clustering. NA, not assessed; MED, medium; ND, not
detected.

Cell Metabolism
Review
at odds with this notion, the activity of SIRT1 depends on NAD+, or whether the plasticity of the acetyl-CoA regulatory network
which also accumulates in the course of oxidative stress can accommodate successful therapeutic interventions.
responses (Houtkooper et al., 2012). A model that reconciles
these findings is missing. Since CASP2 can be found both in AUTHOR CONTRIBUTIONS
the nucleus and in the cytoplasm, subcellular compartmentaliza-
tion may play a hitherto unrecognized role in this process. F.P. and L.G. wrote the review based on the initial draft by F.M. and G.K., de-
signed the table, and supervised the generation of figures; J.M.B.-S.P. created
Irrespective of such a conundrum, these findings suggest a tight
figures and helped with the finalization of the text; F.M. and G.K. conceived the
link between acetyl-CoA metabolism, acetylation reactions, review, wrote a preliminary draft of it, and provided senior supervision to its
and RCD. preparation.
Conclusions and Perspectives ACKNOWLEDGMENTS

Acetyl-CoA regulates several cellular processes as it controls the
balance between anabolic and catabolic reactions, both as a We are indebted to David P. Enot (Gustave Roussy Comprehensive Cancer
Institute) for help with bioinformatics analyses. G.K. is supported by the Ligue
central metabolic intermediate and as a signal transducer.
contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR)—
Perhaps only ATP and NADH share with acetyl-CoA such a Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on
key position in cell biology. Indeed, acetyl-CoA not only is the Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéro-
substrate, intermediate, or product of vital bioenergetic cir- pôle Ile-de-France; Institut National du Cancer (INCa); Fondation Betten-
court-Schueller; Fondation de France; Fondation pour la Recherche Médicale
cuitries, but also regulates several enzymes allosterically and in- (FRM); the European Commission (ArtForce); the European Research Council
fluences the activity of a wide panel of processes (including gene (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA
expression) via (de)acetylation reactions. In this respect, three Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer
Research and Personalized Medicine (CARPEM); and the Paris Alliance of
features render acetyl-CoA unique, namely that (1) its abun- Cancer Research Institutes (PACRI). F.M. is grateful to the Austrian Science
dance dictates one of the quantitatively and functionally most Fund FWF (Austria) for grants P2349-B12, P24381-B20, I1000, and ‘‘SFB
important post-translational modifications that affect eukaryotic Lipotox’’ and to the BMWFW and the Karl Franzens University for grant
proteins, (2) it is subjected to a rigorous subcellular compartmen- ‘‘Unkonventionelle Forschung.’’
talization, adding refinement to its regulatory impact, and (3) its

REFERENCES
concentration and subcellular fluxes are subjected to strong
quantitative changes upon variations in its synthesis and use. Abozguia, K., Clarke, K., Lee, L., and Frenneaux, M. (2006). Modification of
Thus, acetyl-CoA levels in different subcellular compartments myocardial substrate use as a therapy for heart failure. Nat. Clin. Pract.
Cardiovasc. Med. 3, 490–498.
may constitute an intracellular gauge of changing microenviron-
mental conditions and ultimately tune the cellular programs of Adina-Zada, A., Zeczycki, T.N., St Maurice, M., Jitrapakdee, S., Cleland,
adaptation to such perturbations. In line with this latter notion, W.W., and Attwood, P.V. (2012). Allosteric regulation of the biotin-dependent
enzyme pyruvate carboxylase by acetyl-CoA. Biochem. Soc. Trans. 40,
the expression levels of proteins involved in acetyl-CoA meta- 567–572.
bolism and transport, as well as in (de)acetylation reactions,
Aluvila, S., Sun, J., Harrison, D.H., Walters, D.E., and Kaplan, R.S. (2010).
exhibit remarkable variations in cells of different histological Inhibitors of the mitochondrial citrate transport protein: validation of the role
origin (Figure 4). Thus, the cellular differentiation and activation of substrate binding residues and discovery of the first purely competitive in-
state might also affect the relative abundance of multiple hibitor. Mol. Pharmacol. 77, 26–34.
acetyl-CoA-relevant enzymes, adding yet another layer of Andersen, J.L., Thompson, J.W., Lindblom, K.R., Johnson, E.S., Yang, C.S.,
complexity to this regulatory network. Lilley, L.R., Freel, C.D., Moseley, M.A., and Kornbluth, S. (2011). A biotin
switch-based proteomics approach identifies 14-3-3z as a target of Sirt1 in
Pharmaceutical agents that influence the acetyl-CoA meta- the metabolic regulation of caspase-2. Mol. Cell 43, 834–842.
bolism are being developed at an accelerating pace (Table 1).
Some HDAC inhibitors including suberanilohydroxamic acid Athar, M., Back, J.H., Tang, X., Kim, K.H., Kopelovich, L., Bickers, D.R., and
Kim, A.L. (2007). Resveratrol: a review of preclinical studies for human cancer
(SAHA, best known as vorinostat) and romidepsin are approved prevention. Toxicol. Appl. Pharmacol. 224, 274–283.
by international regulatory agencies for use in cancer patients
Baur, J.A., and Sinclair, D.A. (2006). Therapeutic potential of resveratrol: the
(Falkenberg and Johnstone, 2014). Inhibitors of acetyl-CoA- in vivo evidence. Nat. Rev. Drug Discov. 5, 493–506.
consuming enzymes like ACACs and KATs are in preclinical
Bender, T., Pena, G., and Martinou, J.C. (2015). Regulation of mitochondrial
development, mostly for the treatment of metabolic syndromes pyruvate uptake by alternative pyruvate carrier complexes. EMBO J. 34,
(Harwood, 2005). The PDC-activating agent DCA is licensed 911–924.
for the treatment of lactic acidosis (as it favors the mitochondrial
Berwick, D.C., Hers, I., Heesom, K.J., Moule, S.K., and Tavare, J.M. (2002).
metabolism of pyruvate at the expense of cytosolic reduction to The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in
lactate) and is being intensively investigated for its antineoplastic primary adipocytes. J. Biol. Chem. 277, 33895–33900.
activity (Galluzzi et al., 2013). Inhibitors of acetyl-CoA-generating Boroughs, L.K., and DeBerardinis, R.J. (2015). Metabolic pathways promoting
enzymes such as ACLY are in clinical development as weight cancer cell survival and growth. Nat. Cell Biol. 17, 351–359.
loss-promoting or anticancer agents (Hatzivassiliou et al., Brautbar, A., and Ballantyne, C.M. (2011). Pharmacological strategies for
2005; Madeo et al., 2014). Along similar lines, ACSS2 inhibitors lowering LDL cholesterol: statins and beyond. Nat. Rev. Cardiol. 8, 253–265.
have been proposed to mediate selective antineoplastic effects,
Browning, J.D., Baxter, J., Satapati, S., and Burgess, S.C. (2012). The effect of
reflecting the dependency of malignant cells on acetate as short-term fasting on liver and skeletal muscle lipid, glucose, and energy meta-
acetyl-CoA precursor (Comerford et al., 2014). The future will bolism in healthy women and men. J. Lipid Res. 53, 577–586.
tell whether these agents are associated with unsustainable tox- Brownsey, R.W., Boone, A.N., Elliott, J.E., Kulpa, J.E., and Lee, W.M. (2006).
icities due to their disruptive effects on acetyl-CoA metabolism Regulation of acetyl-CoA carboxylase. Biochem. Soc. Trans. 34, 223–227.

Cell Metabolism
Review
Cahill, G.F., Jr. (2006). Fuel metabolism in starvation. Annu. Rev. Nutr. Eisenberg, T., Schroeder, S., Andryushkova, A., Pendl, T., Küttner, V., Bhukel,
26, 1–22. A., Mariño, G., Pietrocola, F., Harger, A., Zimmermann, A., et al. (2014). Nucle-
ocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates
Cai, L., Sutter, B.M., Li, B., and Tu, B.P. (2011). Acetyl-CoA induces cell growth autophagy and prolongs lifespan. Cell Metab. 19, 431–444.
and proliferation by promoting the acetylation of histones at growth genes.
Mol. Cell 42, 426–437. Falkenberg, K.J., and Johnstone, R.W. (2014). Histone deacetylases and their
inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev.
Casero, R.A., Jr., and Marton, L.J. (2007). Targeting polyamine metabolism Drug Discov. 13, 673–691.
and function in cancer and other hyperproliferative diseases. Nat. Rev. Drug
Discov. 6, 373–390. Franken, J., Kroppenstedt, S., Swiegers, J.H., and Bauer, F.F. (2008). Carnitine
and carnitine acetyltransferases in the yeast Saccharomyces cerevisiae: a role
Cederbaum, A.I. (2012). Alcohol metabolism. Clin. Liver Dis. 16, 667–685. for carnitine in stress protection. Curr. Genet. 53, 347–360.
Chang, H.C., and Guarente, L. (2014). SIRT1 and other sirtuins in metabolism. Fritz, K.S., Green, M.F., Petersen, D.R., and Hirschey, M.D. (2013). Ethanol
Trends Endocrinol. Metab. 25, 138–145. metabolism modifies hepatic protein acylation in mice. PLoS ONE 8, e75868.
Chen, Y., Siewers, V., and Nielsen, J. (2012). Profiling of cytosolic and perox- Frost, G., Sleeth, M.L., Sahuri-Arisoylu, M., Lizarbe, B., Cerdan, S., Brody, L.,
isomal acetyl-CoA metabolism in Saccharomyces cerevisiae. PLoS ONE 7, Anastasovska, J., Ghourab, S., Hankir, M., Zhang, S., et al. (2014). The short-
e42475. chain fatty acid acetate reduces appetite via a central homeostatic mecha-
nism. Nat. Commun. 5, 3611.
Cheng, C.W., Adams, G.B., Perin, L., Wei, M., Zhou, X., Lam, B.S., Da Sacco,
S., Mirisola, M., Quinn, D.I., Dorff, T.B., et al. (2014). Prolonged fasting reduces Fujino, T., Kondo, J., Ishikawa, M., Morikawa, K., and Yamamoto, T.T. (2001).
IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxida-
reverse immunosuppression. Cell Stem Cell 14, 810–823. tion of acetate. J. Biol. Chem. 276, 11420–11426.
Choudhary, C., Weinert, B.T., Nishida, Y., Verdin, E., and Mann, M. (2014). The Galluzzi, L., Kepp, O., Vander Heiden, M.G., and Kroemer, G. (2013). Metabolic
growing landscape of lysine acetylation links metabolism and cell signalling. targets for cancer therapy. Nat. Rev. Drug Discov. 12, 829–846.
Nat. Rev. Mol. Cell Biol. 15, 536–550.
Galluzzi, L., Bravo-San Pedro, J.M., and Kroemer, G. (2014). Organelle-spe-
Chow, J.D., Lawrence, R.T., Healy, M.E., Dominy, J.E., Liao, J.A., Breen, D.S., cific initiation of cell death. Nat. Cell Biol. 16, 728–736.
Byrne, F.L., Kenwood, B.M., Lackner, C., Okutsu, S., et al. (2014). Genetic in-
hibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters Galluzzi, L., Bravo-San Pedro, J.M., Vitale, I., Aaronson, S.A., Abrams, J.M.,
global protein acetylation. Mol Metab 3, 419–431. Adam, D., Alnemri, E.S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli,
M., et al. (2015a). Essential versus accessory aspects of cell death: recom-
Comerford, S.A., Huang, Z., Du, X., Wang, Y., Cai, L., Witkiewicz, A.K., Wal- mendations of the NCCD 2015. Cell Death Differ. 22, 58–73.
ters, H., Tantawy, M.N., Fu, A., Manning, H.C., et al. (2014). Acetate depen-
dence of tumors. Cell 159, 1591–1602. Galluzzi, L., Pietrocola, F., Bravo-San Pedro, J.M., Amaravadi, R.K., Baeh-
recke, E.H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D.A., Karantza,
Cotter, D.G., Schugar, R.C., and Crawford, P.A. (2013). Ketone body meta- V., et al. (2015b). Autophagy in malignant transformation and cancer progres-
bolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, sion. EMBO J. 34, 856–880.
H1060–H1076.
Grassian, A.R., Parker, S.J., Davidson, S.M., Divakaruni, A.S., Green, C.R.,
Damiano, F., Tocci, R., Gnoni, G.V., and Siculella, L. (2015). Expression of cit- Zhang, X., Slocum, K.L., Pu, M., Lin, F., Vickers, C., et al. (2014). IDH1 muta-
rate carrier gene is activated by ER stress effectors XBP1 and ATF6a, binding tions alter citric acid cycle metabolism and increase dependence on oxidative
to an UPRE in its promoter. Biochim. Biophys. Acta 1849, 23–31. mitochondrial metabolism. Cancer Res. 74, 3317–3331.
Davenport, A.M., Collins, L.N., Chiu, H., Minor, P.J., Sternberg, P.W., and Green, D.R., Galluzzi, L., and Kroemer, G. (2011). Mitochondria and the auto-
Hoelz, A. (2014). Structural and functional characterization of the a-tubulin phagy-inflammation-cell death axis in organismal aging. Science 333, 1109–
acetyltransferase MEC-17. J. Mol. Biol. 426, 2605–2616. 1112.
Demierre, M.F., Higgins, P.D., Gruber, S.B., Hawk, E., and Lippman, S.M. Green, D.R., Galluzzi, L., and Kroemer, G. (2014). Cell biology. Metabolic con-
(2005). Statins and cancer prevention. Nat. Rev. Cancer 5, 930–942. trol of cell death. Science 345, 1250256.
Denisov, I.G., and Sligar, S.G. (2012). A novel type of allosteric regulation: Greer, C., Lee, M., Westerhof, M., Milholland, B., Spokony, R., Vijg, J., and
functional cooperativity in monomeric proteins. Arch. Biochem. Biophys. Secombe, J. (2013). Myc-dependent genome instability and lifespan in
519, 91–102. Drosophila. PLoS ONE 8, e74641.
Ding, Y., Dellisanti, C.D., Ko, M.H., Czajkowski, C., and Puglielli, L. (2014). The Guarente, L. (2013). Calorie restriction and sirtuins revisited. Genes Dev. 27,
endoplasmic reticulum-based acetyltransferases, ATase1 and ATase2, asso- 2072–2085.
ciate with the oligosaccharyltransferase to acetylate correctly folded polypep-
tides. J. Biol. Chem. 289, 32044–32055. Hait, N.C., Allegood, J., Maceyka, M., Strub, G.M., Harikumar, K.B., Singh,
S.K., Luo, C., Marmorstein, R., Kordula, T., Milstien, S., and Spiegel, S.
Dittenhafer-Reed, K.E., Richards, A.L., Fan, J., Smallegan, M.J., Fotuhi Siah- (2009). Regulation of histone acetylation in the nucleus by sphingosine-1-
pirani, A., Kemmerer, Z.A., Prolla, T.A., Roy, S., Coon, J.J., and Denu, J.M. phosphate. Science 325, 1254–1257.
(2015). SIRT3 Mediates Multi-Tissue Coupling for Metabolic Fuel Switching.
Cell Metab. 21, 637–646. Halestrap, A.P., and Price, N.T. (1999). The proton-linked monocarboxylate
transporter (MCT) family: structure, function and regulation. Biochem. J.
Donohoe, D.R., Collins, L.B., Wali, A., Bigler, R., Sun, W., and Bultman, S.J. 343, 281–299.
(2012). The Warburg effect dictates the mechanism of butyrate-mediated his-
tone acetylation and cell proliferation. Mol. Cell 48, 612–626. Harris, R.A., Joshi, M., Jeoung, N.H., and Obayashi, M. (2005). Overview of the
molecular and biochemical basis of branched-chain amino acid catabolism.
Durán, R.V., Oppliger, W., Robitaille, A.M., Heiserich, L., Skendaj, R., Gottlieb, J. Nutr. 135, 1527S–1530S.
E., and Hall, M.N. (2012). Glutaminolysis activates Rag-mTORC1 signaling.
Mol. Cell 47, 349–358. Harwood, H.J., Jr. (2005). Treating the metabolic syndrome: acetyl-CoA
carboxylase inhibition. Expert Opin. Ther. Targets 9, 267–281.
Edmunds, L.R., Sharma, L., Kang, A., Lu, J., Vockley, J., Basu, S., Uppala, R.,
Goetzman, E.S., Beck, M.E., Scott, D., and Prochownik, E.V. (2014). c-Myc Hatzivassiliou, G., Zhao, F., Bauer, D.E., Andreadis, C., Shaw, A.N., Dhanak,
programs fatty acid metabolism and dictates acetyl-CoA abundance and D., Hingorani, S.R., Tuveson, D.A., and Thompson, C.B. (2005). ATP citrate
fate. J. Biol. Chem. 289, 25382–25392. lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321.
Edwards, P.A., and Ericsson, J. (1999). Sterols and isoprenoids: signaling He, C., Bassik, M.C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher,
molecules derived from the cholesterol biosynthetic pathway. Annu. Rev. J., Sun, Q., et al. (2012). Exercise-induced BCL2-regulated autophagy is
Biochem. 68, 157–185. required for muscle glucose homeostasis. Nature 481, 511–515.

Cell Metabolism
Review
Hebert, A.S., Dittenhafer-Reed, K.E., Yu, W., Bailey, D.J., Selen, E.S., transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am. J.
Boersma, M.D., Carson, J.J., Tonelli, M., Balloon, A.J., Higbee, A.J., et al. Hum. Genet. 83, 752–759.
(2013). Calorie restriction and SIRT3 trigger global reprogramming of the mito-
chondrial protein acetylome. Mol. Cell 49, 186–199. Lundby, A., Lage, K., Weinert, B.T., Bekker-Jensen, D.B., Secher, A., Skov-
gaard, T., Kelstrup, C.D., Dmytriyev, A., Choudhary, C., Lundby, C., and Olsen,
Henry, R.A., Kuo, Y.M., Bhattacharjee, V., Yen, T.J., and Andrews, A.J. (2015). J.V. (2012). Proteomic analysis of lysine acetylation sites in rat tissues reveals
Changing the selectivity of p300 by acetyl-CoA modulation of histone acetyla- organ specificity and subcellular patterns. Cell Rep. 2, 419–431.
tion. ACS Chem. Biol. 10, 146–156.
Lundquist, F., Tygstrup, N., Winkler, K., Mellemgaard, K., and Munck-
Herzig, S., Raemy, E., Montessuit, S., Veuthey, J.L., Zamboni, N., Wester- Petersen, S. (1962). Ethanol metabolism and production of free acetate in
mann, B., Kunji, E.R., and Martinou, J.C. (2012). Identification and functional the human liver. J. Clin. Invest. 41, 955–961.
expression of the mitochondrial pyruvate carrier. Science 337, 93–96.
Madeo, F., Pietrocola, F., Eisenberg, T., and Kroemer, G. (2014). Caloric re-
Hofmann, J.W., Zhao, X., De Cecco, M., Peterson, A.L., Pagliaroli, L., Mani- striction mimetics: towards a molecular definition. Nat. Rev. Drug Discov.
vannan, J., Hubbard, G.B., Ikeno, Y., Zhang, Y., Feng, B., et al. (2015). 13, 727–740.
Reduced expression of MYC increases longevity and enhances healthspan.
Cell 160, 477–488. Madiraju, P., Pande, S.V., Prentki, M., and Madiraju, S.R. (2009). Mitochondrial
acetylcarnitine provides acetyl groups for nuclear histone acetylation. Epige-
Hollebeke, J., Van Damme, P., and Gevaert, K. (2012). N-terminal acetylation netics 4, 399–403.
and other functions of Na-acetyltransferases. Biol. Chem. 393, 291–298.
Makrecka, M., Svalbe, B., Volska, K., Sevostjanovs, E., Liepins, J., Grinberga,
Houtkooper, R.H., Pirinen, E., and Auwerx, J. (2012). Sirtuins as regulators of S., Pugovics, O., Liepinsh, E., and Dambrova, M. (2014). Mildronate, the inhib-
metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238. itor of L-carnitine transport, induces brain mitochondrial uncoupling and pro-
tects against anoxia-reoxygenation. Eur. J. Pharmacol. 723, 55–61.
Huang, H., Liu, N., Yang, C., Liao, S., Guo, H., Zhao, K., Li, X., Liu, S., Guan, L.,
Liu, C., et al. (2012). HDAC inhibitor L-carnitine and proteasome inhibitor bor- Mariño, G., Pietrocola, F., Eisenberg, T., Kong, Y., Malik, S.A., Andryushkova,
tezomib synergistically exert anti-tumor activity in vitro and in vivo. PLoS ONE A., Schroeder, S., Pendl, T., Harger, A., Niso-Santano, M., et al. (2014). Regu-
7, e52576. lation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725.
Huang, R., Xu, Y., Wan, W., Shou, X., Qian, J., You, Z., Liu, B., Chang, C., Zhou, Martinez-Pastor, B., Cosentino, C., and Mostoslavsky, R. (2013). A tale of me-
T., Lippincott-Schwartz, J., and Liu, W. (2015). Deacetylation of nuclear LC3 tabolites: the cross-talk between chromatin and energy metabolism. Cancer
drives autophagy initiation under starvation. Mol. Cell 57, 456–466. Discov 3, 497–501.
Infantino, V., Iacobazzi, V., Menga, A., Avantaggiati, M.L., and Palmieri, F. Mashimo, T., Pichumani, K., Vemireddy, V., Hatanpaa, K.J., Singh, D.K., Sira-
(2014). A key role of the mitochondrial citrate carrier (SLC25A1) in TNFa- sanagandla, S., Nannepaga, S., Piccirillo, S.G., Kovacs, Z., Foong, C., et al.
and IFNg-triggered inflammation. Biochim. Biophys. Acta 1839, 1217–1225. (2014). Acetate is a bioenergetic substrate for human glioblastoma and brain
metastases. Cell 159, 1603–1614.
Kamphorst, J.J., Chung, M.K., Fan, J., and Rabinowitz, J.D. (2014). Quantita-
tive analysis of acetyl-CoA production in hypoxic cancer cells reveals substan- McBrian, M.A., Behbahan, I.S., Ferrari, R., Su, T., Huang, T.W., Li, K., Hong,
tial contribution from acetate. Cancer Metab 2, 23. C.S., Christofk, H.R., Vogelauer, M., Seligson, D.B., and Kurdistani, S.K.
(2013). Histone acetylation regulates intracellular pH. Mol. Cell 49, 310–321.
Kanamori, A., Nakayama, J., Fukuda, M.N., Stallcup, W.B., Sasaki, K., Fukuda,
M., and Hirabayashi, Y. (1997). Expression cloning and characterization of a McCoy, F., Darbandi, R., Lee, H.C., Bharatham, K., Moldoveanu, T., Grace,
cDNA encoding a novel membrane protein required for the formation of C.R., Dodd, K., Lin, W., Chen, S.I., Tangallapally, R.P., et al. (2013). Metabolic
O-acetylated ganglioside: a putative acetyl-CoA transporter. Proc. Natl. activation of CaMKII by coenzyme A. Mol. Cell 52, 325–339.
Acad. Sci. USA 94, 2897–2902.
Mehrotra, S., Galdieri, L., Zhang, T., Zhang, M., Pemberton, L.F., and Vancura,
Kim, D.H., Park, M.H., Lee, E.K., Choi, Y.J., Chung, K.W., Moon, K.M., Kim, A. (2014). Histone hypoacetylation-activated genes are repressed by acetyl-
M.J., An, H.J., Park, J.W., Kim, N.D., et al. (2015). The roles of FoxOs in mod- CoA- and chromatin-mediated mechanism. Biochim. Biophys. Acta 1839,
ulation of aging by calorie restriction. Biogerontology 16, 1–14. 751–763.
Koves, T.R., Ussher, J.R., Noland, R.C., Slentz, D., Mosedale, M., Ilkayeva, O., Metallo, C.M., Gameiro, P.A., Bell, E.L., Mattaini, K.R., Yang, J., Hiller, K., Jew-
Bain, J., Stevens, R., Dyck, J.R., Newgard, C.B., et al. (2008). Mitochondrial ell, C.M., Johnson, Z.R., Irvine, D.J., Guarente, L., et al. (2012). Reductive
overload and incomplete fatty acid oxidation contribute to skeletal muscle in- glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature
sulin resistance. Cell Metab. 7, 45–56. 481, 380–384.
Kraus, D., Yang, Q., Kong, D., Banks, A.S., Zhang, L., Rodgers, J.T., Pirinen, Mizuarai, S., Miki, S., Araki, H., Takahashi, K., and Kotani, H. (2005). Identifica-
E., Pulinilkunnil, T.C., Gong, F., Wang, Y.C., et al. (2014). Nicotinamide tion of dicarboxylate carrier Slc25a10 as malate transporter in de novo fatty
N-methyltransferase knockdown protects against diet-induced obesity. acid synthesis. J. Biol. Chem. 280, 32434–32441.
Nature 508, 258–262.
Moffett, J.R., Arun, P., Ariyannur, P.S., and Namboodiri, A.M. (2013). N-Acety-
Kuhn, M.L., Zemaitaitis, B., Hu, L.I., Sahu, A., Sorensen, D., Minasov, G., Lima, laspartate reductions in brain injury: impact on post-injury neuroenergetics,
B.P., Scholle, M., Mrksich, M., Anderson, W.F., et al. (2014). Structural, kinetic lipid synthesis, and protein acetylation. Front Neuroenergetics 5, 11.
and proteomic characterization of acetyl phosphate-dependent bacterial pro-
tein acetylation. PLoS ONE 9, e94816. Morrish, F., Noonan, J., Perez-Olsen, C., Gafken, P.R., Fitzgibbon, M., Kel-
leher, J., VanGilst, M., and Hockenbery, D. (2010). Myc-dependent mitochon-
Kunze, M., Pracharoenwattana, I., Smith, S.M., and Hartig, A. (2006). A central drial generation of acetyl-CoA contributes to fatty acid biosynthesis and
role for the peroxisomal membrane in glyoxylate cycle function. Biochim. histone acetylation during cell cycle entry. J. Biol. Chem. 285, 36267–36274.
Biophys. Acta 1763, 1441–1452.
Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras,
Langer, M.R., Fry, C.J., Peterson, C.L., and Denu, J.M. (2002). Modulating K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., et al. (2010). Caloric restriction
acetyl-CoA binding in the GCN5 family of histone acetyltransferases. J. Biol. and resveratrol promote longevity through the Sirtuin-1-dependent induction
Chem. 277, 27337–27344. of autophagy. Cell Death Dis. 1, e10.
Lee, J.V., Shah, S.A., and Wellen, K.E. (2013). Obesity, cancer, and acetyl-CoA Moussaieff, A., Rouleau, M., Kitsberg, D., Cohen, M., Levy, G., Barasch, D.,
metabolism. Drug Discov. Today Dis. Mech. 10, e55–e61. Nemirovski, A., Shen-Orr, S., Laevsky, I., Amit, M., et al. (2015). Glycolysis-
mediated changes in acetyl-CoA and histone acetylation control the early dif-
Lee, J.V., Carrer, A., Shah, S., Snyder, N.W., Wei, S., Venneti, S., Worth, A.J., ferentiation of embryonic stem cells. Cell Metab. 21, 392–402.
Yuan, Z.F., Lim, H.W., Liu, S., et al. (2014). Akt-dependent metabolic reprog-
ramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319. Mullen, A.R., Wheaton, W.W., Jin, E.S., Chen, P.H., Sullivan, L.B., Cheng, T.,
Yang, Y., Linehan, W.M., Chandel, N.S., and DeBerardinis, R.J. (2012). Reduc-
Lin, P., Li, J., Liu, Q., Mao, F., Li, J., Qiu, R., Hu, H., Song, Y., Yang, Y., Gao, G., tive carboxylation supports growth in tumour cells with defective mitochon-
et al. (2008). A missense mutation in SLC33A1, which encodes the acetyl-CoA dria. Nature 481, 385–388.

Cell Metabolism
Review
Muoio, D.M., Noland, R.C., Kovalik, J.P., Seiler, S.E., Davies, M.N., DeBalsi, Scott, I., Webster, B.R., Chan, C.K., Okonkwo, J.U., Han, K., and Sack, M.N.
K.L., Ilkayeva, O.R., Stevens, R.D., Kheterpal, I., Zhang, J., et al. (2012). Mus- (2014). GCN5-like protein 1 (GCN5L1) controls mitochondrial content through
cle-specific deletion of carnitine acetyltransferase compromises glucose toler- coordinated regulation of mitochondrial biogenesis and mitophagy. J. Biol.
ance and metabolic flexibility. Cell Metab. 15, 764–777. Chem. 289, 2864–2872.
Newman, J.C., and Verdin, E. (2014). Ketone bodies as signaling metabolites. Shan, C., Elf, S., Ji, Q., Kang, H.B., Zhou, L., Hitosugi, T., Jin, L., Lin, R., Zhang,
Trends Endocrinol. Metab. 25, 42–52. L., Seo, J.H., et al. (2014). Lysine acetylation activates 6-phosphogluconate
dehydrogenase to promote tumor growth. Mol. Cell 55, 552–565.
Nitschke, W., and Russell, M.J. (2013). Beating the acetyl coenzyme
A-pathway to the origin of life. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, Shi, L., and Tu, B.P. (2013). Acetyl-CoA induces transcription of the key G1
20120258. cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces
cerevisiae. Proc. Natl. Acad. Sci. USA 110, 7318–7323.
Nutt, L.K., Buchakjian, M.R., Gan, E., Darbandi, R., Yoon, S.Y., Wu, J.Q., Miya-
moto, Y.J., Gibbons, J.A., Andersen, J.L., Freel, C.D., et al. (2009). Metabolic Shi, L., and Tu, B.P. (2015). Acetyl-CoA and the regulation of metabolism:
control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphory- mechanisms and consequences. Curr. Opin. Cell Biol. 33, 125–131.
lation of caspase-2. Dev. Cell 16, 856–866.
Shimazu, T., Hirschey, M.D., Newman, J., He, W., Shirakawa, K., Le Moan, N.,
Overmyer, K.A., Evans, C.R., Qi, N.R., Minogue, C.E., Carson, J.J., Cherm- Grueter, C.A., Lim, H., Saunders, L.R., Stevens, R.D., et al. (2013). Suppres-
side-Scabbo, C.J., Koch, L.G., Britton, S.L., Pagliarini, D.J., Coon, J.J., and sion of oxidative stress by b-hydroxybutyrate, an endogenous histone deace-
Burant, C.F. (2015). Maximal oxidative capacity during exercise is associated tylase inhibitor. Science 339, 211–214.
with skeletal muscle fuel selection and dynamic changes in mitochondrial pro-
tein acetylation. Cell Metab. 21, 468–478. Strittmatter, L., Li, Y., Nakatsuka, N.J., Calvo, S.E., Grabarek, Z., and Mootha,
V.K. (2014). CLYBL is a polymorphic human enzyme with malate synthase and
Pardee, T.S., Lee, K., Luddy, J., Maturo, C., Rodriguez, R., Isom, S., Miller, b-methylmalate synthase activity. Hum. Mol. Genet. 23, 2313–2323.
L.D., Stadelman, K.M., Levitan, D., Hurd, D., et al. (2014). A phase I study of
the first-in-class antimitochondrial metabolism agent, CPI-613, in patients Sutendra, G., Kinnaird, A., Dromparis, P., Paulin, R., Stenson, T.H., Haromy,
with advanced hematologic malignancies. Clin. Cancer Res. 20, 5255–5264. A., Hashimoto, K., Zhang, N., Flaim, E., and Michelakis, E.D. (2014). A nuclear
pyruvate dehydrogenase complex is important for the generation of acetyl-
Patel, M.S., Nemeria, N.S., Furey, W., and Jordan, F. (2014). The pyruvate de- CoA and histone acetylation. Cell 158, 84–97.
hydrogenase complexes: structure-based function and regulation. J. Biol.
Chem. 289, 16615–16623. Szutowicz, A., Bielarczyk, H., Jankowska-Kulawy, A., Pawe1czyk, T., and
Ronowska, A. (2013). Acetyl-CoA the key factor for survival or death of cholin-
Pegg, A.E. (2008). Spermidine/spermine-N(1)-acetyltransferase: a key meta- ergic neurons in course of neurodegenerative diseases. Neurochem. Res. 38,
bolic regulator. Am. J. Physiol. Endocrinol. Metab. 294, E995–E1010. 1523–1542.
Pehar, M., and Puglielli, L. (2013). Lysine acetylation in the lumen of the ER: a Takahashi, H., McCaffery, J.M., Irizarry, R.A., and Boeke, J.D. (2006). Nucleo-
novel and essential function under the control of the UPR. Biochim. Biophys. cytosolic acetyl-coenzyme a synthetase is required for histone acetylation and
Acta 1833, 686–697. global transcription. Mol. Cell 23, 207–217.
Pehar, M., Lehnus, M., Karst, A., and Puglielli, L. (2012). Proteomic assess- Tang, Y., Zhao, W., Chen, Y., Zhao, Y., and Gu, W. (2008). Acetylation is indis-
ment shows that many endoplasmic reticulum (ER)-resident proteins are pensable for p53 activation. Cell 133, 612–626.
targeted by N(epsilon)-lysine acetylation in the lumen of the organelle and pre-
dicts broad biological impact. J. Biol. Chem. 287, 22436–22440. Tanner, K.G., Langer, M.R., Kim, Y., and Denu, J.M. (2000). Kinetic mechanism
of the histone acetyltransferase GCN5 from yeast. J. Biol. Chem. 275, 22048–
Peng, Y., Li, M., Clarkson, B.D., Pehar, M., Lao, P.J., Hillmer, A.T., Barnhart, 22055.
T.E., Christian, B.T., Mitchell, H.A., Bendlin, B.B., et al. (2014). Deficient import
of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to Travers, M.T., and Barber, M.C. (1997). Tissue-specific control of the acetyl-
infections, inflammation, and cancer. J. Neurosci. 34, 6772–6789. CoA carboxylase gene. Biochem. Soc. Trans. 25, 1215–1219.
Perry, R.J., Zhang, X.M., Zhang, D., Kumashiro, N., Camporez, J.P., Cline, Tsuchiya, Y., Pham, U., Hu, W., Ohnuma, S., and Gout, I. (2014). Changes in
G.W., Rothman, D.L., and Shulman, G.I. (2014). Leptin reverses diabetes by acetyl CoA levels during the early embryonic development of Xenopus laevis.
suppression of the hypothalamic-pituitary-adrenal axis. Nat. Med. 20, PLoS ONE 9, e97693.
759–763.
van der Horst, A., and Burgering, B.M. (2007). Stressing the role of FoxO pro-
Pietrocola, F., Izzo, V., Niso-Santano, M., Vacchelli, E., Galluzzi, L., Maiuri, teins in lifespan and disease. Nat. Rev. Mol. Cell Biol. 8, 440–450.
M.C., and Kroemer, G. (2013). Regulation of autophagy by stress-responsive
transcription factors. Semin. Cancer Biol. 23, 310–322. Violante, S., Ijlst, L., Ruiter, J., Koster, J., van Lenthe, H., Duran, M., de Almeida,
I.T., Wanders, R.J., Houten, S.M., and Ventura, F.V. (2013). Substrate specificity
Pietrocola, F., Lachkar, S., Enot, D.P., Niso-Santano, M., Bravo-San Pedro, of human carnitine acetyltransferase: Implications for fatty acid and branched-
J.M., Sica, V., Izzo, V., Maiuri, M.C., Madeo, F., Mariño, G., and Kroemer, G. chain amino acid metabolism. Biochim. Biophys. Acta 1832, 773–779.
(2015). Spermidine induces autophagy by inhibiting the acetyltransferase
EP300. Cell Death Differ. 22, 509–516. Wagner, G.R., and Payne, R.M. (2013). Widespread and enzyme-independent
Nε-acetylation and Nε-succinylation of proteins in the chemical conditions of
Pozefsky, T., Tancredi, R.G., Moxley, R.T., Dupre, J., and Tobin, J.D. (1976). the mitochondrial matrix. J. Biol. Chem. 288, 29036–29045.
Effects of brief starvation on muscle amino acid metabolism in nonobese
man. J. Clin. Invest. 57, 444–449. Wallace, D.C. (2012). Mitochondria and cancer. Nat. Rev. Cancer 12, 685–698.
Rebouche, C.J., and Seim, H. (1998). Carnitine metabolism and its regulation Webster, B.R., Scott, I., Han, K., Li, J.H., Lu, Z., Stevens, M.V., Malide, D.,
in microorganisms and mammals. Annu. Rev. Nutr. 18, 39–61. Chen, Y., Samsel, L., Connelly, P.S., et al. (2013). Restricted mitochondrial
protein acetylation initiates mitochondrial autophagy. J. Cell Sci. 126, 4843–
Rufer, A.C., Thoma, R., and Hennig, M. (2009). Structural insight into function 4849.
and regulation of carnitine palmitoyltransferase. Cell. Mol. Life Sci. 66, 2489–
2501. Weinert, B.T., Iesmantavicius, V., Moustafa, T., Schölz, C., Wagner, S.A.,
Magnes, C., Zechner, R., and Choudhary, C. (2014). Acetylation dynamics
Sahar, S., Masubuchi, S., Eckel-Mahan, K., Vollmer, S., Galla, L., Ceglia, N., and stoichiometry in Saccharomyces cerevisiae. Mol. Syst. Biol. 10, 716.
Masri, S., Barth, T.K., Grimaldi, B., Oluyemi, O., et al. (2014). Circadian control
of fatty acid elongation by SIRT1 protein-mediated deacetylation of acetyl- Wellen, K.E., Hatzivassiliou, G., Sachdeva, U.M., Bui, T.V., Cross, J.R., and
coenzyme A synthetase 1. J. Biol. Chem. 289, 6091–6097. Thompson, C.B. (2009). ATP-citrate lyase links cellular metabolism to histone
acetylation. Science 324, 1076–1080.
Schug, Z.T., Peck, B., Jones, D.T., Zhang, Q., Grosskurth, S., Alam, I.S.,
Goodwin, L.M., Smethurst, E., Mason, S., Blyth, K., et al. (2015). Acetyl-CoA Wieman, H.L., Wofford, J.A., and Rathmell, J.C. (2007). Cytokine stimulation
synthetase 2 promotes acetate utilization and maintains cancer cell growth un- promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of
der metabolic stress. Cancer Cell 27, 57–71. Glut1 activity and trafficking. Mol. Biol. Cell 18, 1437–1446.

Cell Metabolism
Review
Xu, Y. (2003). Regulation of p53 responses by post-translational modifications. Yi, C.H., Pan, H., Seebacher, J., Jang, I.H., Hyberts, S.G., Heffron, G.J., Van-
Cell Death Differ. 10, 400–403. der Heiden, M.G., Yang, R., Li, F., Locasale, J.W., et al. (2011). Metabolic regu-
lation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell 146,
Xu, M., Nagati, J.S., Xie, J., Li, J., Walters, H., Moon, Y.A., Gerard, R.D., 607–620.
Huang, C.L., Comerford, S.A., Hammer, R.E., et al. (2014). An acetate switch
regulates stress erythropoiesis. Nat. Med. 20, 1018–1026. Zaidi, N., Swinnen, J.V., and Smans, K. (2012). ATP-citrate lyase: a key player
in cancer metabolism. Cancer Res. 72, 3709–3714.
Yang, C., Ko, B., Hensley, C.T., Jiang, L., Wasti, A.T., Kim, J., Sudderth, J.,
Calvaruso, M.A., Lumata, L., Mitsche, M., et al. (2014). Glutamine oxidation Zeng, L., Zhang, Q., Li, S., Plotnikov, A.N., Walsh, M.J., and Zhou, M.M. (2010).
maintains the TCA cycle and cell survival during impaired mitochondrial pyru- Mechanism and regulation of acetylated histone binding by the tandem PHD
vate transport. Mol. Cell 56, 414–424. finger of DPF3b. Nature 466, 258–262.
Yennawar, N.H., Islam, M.M., Conway, M., Wallin, R., and Hutson, S.M. (2006). Zhang, M., Galdieri, L., and Vancura, A. (2013). The yeast AMPK homolog
Human mitochondrial branched chain aminotransferase isozyme: structural SNF1 regulates acetyl coenzyme A homeostasis and histone acetylation.
role of the CXXC center in catalysis. J. Biol. Chem. 281, 39660–39671. Mol. Cell. Biol. 33, 4701–4717.

Aula 8 - Acetyl-CoA

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Licenciado para - Paulo Sérgio Martins dos Santos - 09609690718 - Protegido por Eduzz.

Acetyl Coenzyme A: A Central

*Correspondence: [email protected] (F.M.), [email protected] (G.K.)

Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct

Introduction Nonetheless, acetylation is mostly studied as a post-transla-

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Figure 1. Mitochondrial and Nucleo-Cytosolic Bioenergetic Metabolism of Acetyl-CoA in Mammalian Cells

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Figure 2. Compartmentalization of Acetyl-CoA Metabolism

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Figure 3. Impact of the Acetyl-CoA/CoA Ratio on Global Cellular Functions

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(legend on next page)

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Table 1. Main Pharmacological Modulators of Acetyl-CoA Metabolism

Figure 4. Expression Levels of Proteins Involved in Acetyl-CoA Metabolism

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Conclusions and Perspectives ACKNOWLEDGMENTS

talization, adding refinement to its regulatory impact, and (3) its

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