Biochimie 135 (2017) 164e172

Contents lists available at ScienceDirect

Biochimie
journal homepage: www.elsevier.com/locate/biochi

Review

Genetic alterations in Krebs cycle and its impact on cancer

pathogenesis
Karishma Sajnani a, 1, Farhadul Islam a, b, 1, Robert Anthony Smith a, c, Vinod Gopalan a, 1,
Alfred King-Yin Lam a, *
a
Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Grifth University, Gold Coast, QLD, Australia
b
Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
c
Genomics Research Centre, Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Queensland,
Australia

a r t i c l e i n f o a b s t r a c t

Article history: Cancer cells exhibit alterations in many cellular processes, including oxygen sensing and energy meta-
Received 9 November 2016 bolism. Glycolysis in non-oxygen condition is the main energy production process in cancer rather than
Received in revised form mitochondrial respiration as in benign cells. Genetic and epigenetic alterations of Krebs cycle enzymes
14 February 2017
favour the shift of cancer cells from oxidative phosphorylation to anaerobic glycolysis. Mutations in
Accepted 16 February 2017
Available online 20 February 2017
genes encoding aconitase, isocitrate dehydrogenase, succinate dehydrogenase, fumarate hydratase, and
citrate synthase are noted in many cancers. Abnormalities of Krebs cycle enzymes cause ectopic pro-
duction of Krebs cycle intermediates (oncometabolites) such as 2-hydroxyglutarate, and citrate. These
Keywords:
Oncometabolites
oncometabolites stabilize hypoxia inducible factor 1 (HIF1), nuclear factor like 2 (Nrf2), inhibit p53 and
Mitochondria prolyl hydroxylase 3 (PDH3) activities as well as regulate DNA/histone methylation, which in turn
Krebs cycle activate cell growth signalling. They also stimulate increased glutaminolysis, glycolysis and production of
TCA cycle reactive oxygen species (ROS). Additionally, genetic alterations in Krebs cycle enzymes are involved with
Cancer metabolism increased fatty acid b-oxidations and epithelial mesenchymal transition (EMT) induction. These altered
Mutations phenomena in cancer could in turn promote carcinogenesis by stimulating cell proliferation and survival.
Overall, epigenetic and genetic changes of Krebs cycle enzymes lead to the production of oncometabolite
intermediates, which are important driving forces of cancer pathogenesis and progression. Under-
standing and applying the knowledge of these mechanisms opens new therapeutic options for patients
with cancer.
2017 Elsevier B.V. and Socit Franaise de Biochimie et Biologie Molculaire (SFBBM). All rights
reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2. Role of mitochondria in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
3. Tricarboxylic acid cycle and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
4. Role of metabolic enzyme of TCA cycle in cancer pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
4.1. Citrate synthase (CS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
4.2. Aconitase (Aco) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
4.3. Isocitrate dehydrogenase mutations (IDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
4.4. Succinate dehydrogenase (SDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
4.5. Fumarate hydratase (FH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
5. Oncometabolites of the TCA cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

* Corresponding author. Grifth Medical School, Gold Coast Campus, Gold Coast,
QLD, 4222, Australia.
E-mail address: a.lam@grifth.edu.au (A.K.-Y. Lam).
1
Equal to rst authors.

http://dx.doi.org/10.1016/j.biochi.2017.02.008
0300-9084/ 2017 Elsevier B.V. and Socit Franaise de Biochimie et Biologie Molculaire (SFBBM). All rights reserved.
 K. Sajnani et al. / Biochimie 135 (2017) 164e172 165

5.1. Citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

5.2. 2-Hydroxy glutarate (2HG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

1. Introduction

Mitochondria are the power generator for cells. In the recent

years, they have been discovered to possess more complex func-
tions, especially in the pathogenesis of cancer [1]. Also, they are
involved in programmed cell death (apoptosis) in multicellular
organisms and regulate uncontrolled cell growth like cancer [2].
There are many therapeutic substances/drugs that can target
mitochondria and act as anticancer, immunosuppressant and
antiviral agents [3]. To make the best use of these recently available
and newly designed drugs to target mitochondria in cancer treat-
ment, we need to understand the mechanisms driven by the me-
tabolites in mitochondria in the pathogenesis of cancer.
In normal cells, glucose processing begins with oxidative
decarboxylation to generate energy and carbon dioxide (CO2) [4]. A
series of reactions, known as the tricarboxylic acid cycle (TCA cy-
cle), citric acid cycle or Krebs cycle are responsible for this oxidation
of glucose [4]. This cycle is the common metabolic pathway for fuel
molecules such as glucose, fatty acids, and amino acids [4]. Most Fig. 1. Abnormalities of Krebs cycle enzymes and metabolites associated with
energy yielding molecules can enter into the TCA cycle as acetyl cancer. Mutations in genes encoding TCA cycle enzymes result in a metabolic shift of
the cells and promote oncogenic transformation. Also, abnormalities of TCA cycle
CoA and this cycle is the principal metabolic process for cells.
enzymes causes accumulation of various oncometabolites ultimately leading to cancer
Biomolecules, for example glucose and fatty acids which have the development and progression. PDC: pyruvate dehydrogenase complex, CS: citrate
potential to be converted to acetyl groups or carboxylic groups synthase, Aco: aconitase, IDH: isocitrate dehydrogenase, OGDC: oxoglutarate dehy-
ultimately enter the TCA cycle for aerobic metabolism, especially drogenase complex, STK: succinate thiokinase, SDH: succinate dehydrogenase, FH:
for catabolism [4]. In oxygenated conditions, pyruvate produced fumarate hydratase, MDH: malate dehydrogenase, NAD/NADH: nicotinamide adenine
dinucleotide, FAD/FADH: avin adenine dinucleotide, CoA: coenzyme A, Pi: inorganic
from glucose is converted to acetyl CoA and enters into the TCA phosphate, GDP/GTP: guanosine di/tri phosphate, Q: coenzyme Q.
cycle for complete oxidation [4].
In 1956, Warburg reported that cancer cells had different
metabolic characteristics [5]. They mainly produce their energy in ago, it was reported by Otto Warburg that mitochondrial dysfunc-
the form of ATP (adenosine tri-phosphate) by the process of tion or defects could be the cause of cancer [4,11]. This observation
glycolysis (a non-oxidative breakdown of glucose in the cytosol of encouraged other researchers to investigate the role of mitochon-
cell) [5,6]. Thus, the energy metabolism of cancer cells shifts to dria in the pathogenesis of different cancers [12e15]. For example,
glycolysis from mitochondrial respiration. One possible reason that reduced mitochondrial genetic content, mitochondrial DNA
this may occur is that mutations in proto-oncogenes and tumour (mtDNA) copy number and oxidative damage to mtDNA were
suppressor genes which could create pseudohypoxia. Pseudohy- associated with the progression of non-small cell lung cancer [16].
poxia is a condition where cells activate oxygen deprivation Also, several studies reported that the expression of mitochondrial
mechanisms despite the presence of optimal oxygen concentra- genes were upregulated in different cancers [17,18].
tions in cancer. This condition results in the accumulation of un- The role of mitochondria in cancer formation appears to result
usual metabolites and other abnormalities in cancer cells [7]. from mutations in enzymes such as isocitrate dehydrogenase,
Recent advancements in genetic sequencing technologies have succinate dehydrogenase and fumarate dehydrogenase; all of them
enabled researchers to discover mutations in genes encoding are signicant TCA cycle enzymes [19,20]. Mutations of genes
metabolic enzymes that may be involved in this process [8]. Studies encoding these enzymes lead to abnormal accumulation of onco-
demonstrated that mutation of the genes involved in energy metabolites of the TCA cycle, which in turn, stimulates the forma-
metabolism (TCA cycle) caused unexpected enzymatic reactions tion and progression of cancer [9,20]. Mitochondrial dysfunctions
and abnormal accumulation of metabolites, termedoncometabo- due to abnormalities of metabolic enzymes and metabolites act as
lites [8,9] (Fig. 1). These oncometabolites in turn, regulate epige- the driving cause of cancer and can act as a second hit in the
netic mechanisms which control cell proliferation and process of cancer metabolic transformation [21,22]. Thus, the
differentiation [9]. mitochondrial abnormalities induce metabolic reprogramming in
cancer cells and increase the use of glycolysis, which in turn, fa-
vours cell survival and proliferation.
2. Role of mitochondria in cancer

Mitochondria are the power house of the cell. They produce the 3. Tricarboxylic acid cycle and cancer
major proportion of cellular energy and ROS, as well as regulating
apoptosis by modulating cytochrome C release through the The primary fuel source for the TCA cycle is acetyl CoA. The
permeability membrane pore complexes [10]. More than 70 years breakdown of one molecule of glucose yields two pyruvate
166 K. Sajnani et al. / Biochimie 135 (2017) 164e172
molecules. Then, acetyl CoA is generated from these pyruvate
molecules with the help of the pyruvate dehydrogenase complex
(PDC) [4]. A carboxyl group is eliminated in this reaction as CO2
molecules [23]. Acetyl groups of acetyl CoA are converted from the
rest of the two carbon moiety of pyruvate. The high energy sub-
stance nicotinamide adenine di-nucleotide (NADH; reduced) is
generated in this stage, which in turn transfers a hydride ion (:H) to
the electron transfer chain of the respiratory system [23]. The high
energy thioester linkage between acetyl moiety of acetyl CoA and
sulfhydryl moiety of b-mercaptoethylamine makes acetyl CoA a
high energy substance [4,24]. Acetyl CoA nally enters into the
TCA cycle to produce energy and CO2.
In the Krebs cycle, oxaloacetate which is a four-carbon com-
pound is combined with another two-carbon acetyl unit to form a
six-carbon citrate (tri-carboxylic acid). Isocitrate (an isomer of cit-
rate) is then converted to a-ketoglutarate, a ve-carbon interme-
diate of the TCA cycle by an oxidative decarboxylation reaction,
catalysed by isocitrate dehydrogenase [23]. Succinate, a four carbon
compound, is then produced from a-ketoglutarate by oxidative
decarboxylation. Succinate is then oxidised and formed another
four-carbon compound fumarate in presence of succinate dehy-
drogenase. In this step, two hydrogen atoms along with their
electrons retransferred to avin adenine dinucleotide (FAD), pro-
ducing FADH2 [23]. Subsequently, a water molecule is added to the
fumarate and generates malate with the help of the enzyme
fumarase [4,23]. Finally oxaloacetate is regenerated from succinate
[4]. Overall, a two-carbon acetyl moiety enters into the TCA cycle
and two carbon atoms exit from the cycle as CO2 molecules. In these
process three hydride ions, and therefore, six electrons are trans-
ferred to three NAD (nicotinamide adenine dinucleotide; oxi-
dised) and two hydrogen atoms (two electrons) are transferred to
one FAD [4,23]. Thus, through the citric acid cycle, cells harvest
high-energy electrons from the carbon skeleton of fuel molecules
and utilize those electrons to generate NADH and FADH2 high-
energy substances. In oxidative phosphorylation, these NADH and
FADH2 are re-oxidised and release the electrons [4,23]. These
electrons are then transferred through the electron-transport chain
and generate a proton gradient across the mitochondrial mem-
brane. The generated proton gradient makes the protons ow
through ATP-synthase to produce adenosine tri-phosphate (ATP)
using adenosine di-phosphate (ADP) and inorganic phosphate (Pi)
[4,23].
Studies demonstrated that abnormalities of the TCA cycle are
associated with different types of cancers [25e27] (Fig. 1). For
example, it was noted that phosphoenolpyruvate carboxykinase, a
regulator of TCA cycle ux, plays a crucial role in promoting cancer
cell growth and proliferation, particularly in colorectal cancer cells
[27]. Phosphoenolpyruvate carboxykinase increases glucose and
glutamine uptake in cancer cells and favours anabolic metabolism
[27]. This metabolic shift is important for highly proliferating cells,
like cancer cells, which continuously require a supply of precursors
for the synthesis of lipids, proteins and nucleic acids [28]. Several
studies also demonstrated that dysfunction of mitochondrial
metabolic pathways such as the TCA cycle and oxidative phos-
phorylation are associated with the conversion of non-neoplastic
mammary epithelial cells to non-metastatic breast carcinoma and
then to the metastatic cancer cells [29e31].
4. Role of metabolic enzyme of TCA cycle in cancer
pathogenesis
Inherited and acquired alteration of TCA cycle enzymes have
been demonstrated in different cancers [32]. There are numerous
alterations of TCA cycle enzymes and metabolites involved in
pathogenesis of cancer (Fig. 2). The changes mainly occur in citrate
synthase (CS) aconitase (ACO2), succinate dehydrogenase (SDH),
fumarate hydratase (FH) and isocitrate dehydrogenase (IDH).
4.1. Citrate synthase (CS)
Citrate synthase (CS) catalyses the conversion of oxaloacetate
and acetyl CoA to citrate (the rst reaction of the Krebs cycle),
which in turn regulates mitochondria mediated energy generation
of cells [23]. Thus, citrate synthase can be assumed as a rate limiting
enzyme of the citric acid cycle. Mutational roles of CS in tumori-
genesis were not studied in depth in the literature. However, Lin
and co-workers reported the functional role of citrate synthase in
cancer metabolism in different types of cancer cells such as Hela,
MCF7 and PC-3 [33]. They demonstrated that suppression of citrate
synthase caused a metabolic shift of cellular bioenergetics from
mitochondrial oxidative phosphorylation to cytosolic glycolysis
[33]. Also, they noted that loss of citrate synthase expression was
associated with the induction of epithelium mesenchymal transi-
tion (EMT) and increased the malignant behaviour of tumours [33].
By contrast, it was demonstrated that citrate synthase was over-
expressed in pancreatic, renal and ovarian cancer when compared
to non-neoplastic cells and tissues [34e36]. In addition, knock-
down of citrate synthase in ovarian cancer cell lines inhibited cell
proliferation, invasion and migration in vitro [34]. Thus, the role of
citrate synthase in cancer metabolism is ambiguous, but genetic
alterations of this critical enzyme may have signicant impact in
cancer pathogenesis and progression in specic cancer subtypes.
However, the specic role that deregulation of citrate synthase
plays in carcinogenesis is not yet clear. The possible underlying
mechanism may be an increase in citrate production by overex-
pressed citrate synthase which could act as a precursor for fatty
acid/lipid synthesis for the cancer cells, which in turn promotes cell
growth and proliferation. The other hypothesis is that the loss of
citrate synthase activity may induce mitochondrial dysfunctions
and could create a tumour-supporting glycolytic switch
microenvironment.
4.2. Aconitase (Aco)
Aconitase (Aco) is an essential enzyme located in the mito-
chondria. It catalyses the reversible isomerization of citrate to iso-
citrate in the TCA cycle [23]. Ternette and colleagues reported that
fumarase hydratase (FH) decient cells had impaired aconitase
synthase 2 enzyme activity [37]. These two alterations (mutation in
FH and impaired Aco2 function) contributed towards hereditary
leiomyomatosis and renal cell carcinoma [37]. Aco2 mutation was
also associated with gastric cancer [38]. Decreased levels of Aco2
have been reported in prostate cancer [39]. In addition, the
decreased level of Aco2 enzyme in prostate cancer was associated
with down regulation of ZIP 1 (Zinc into prostate). ZIP 1 is a zinc
transporter which could cause depletion of zinc in prostate cancer.
This phenomenon leads to metabolic transformation of prostate
cells by impairing the citrate oxidation and stimulates the conver-
sion of citrate secretory non-neoplastic epithelial cells to citrate
oxidizing prostatic carcinoma cells [39].
4.3. Isocitrate dehydrogenase mutations (IDH)
In the second steps of the TCA cycle, isocitrate dehydrogenase
(IDH) catalyses the conversion of isocitrate to a-ketoglutarate
which is an oxidative decarboxylation reaction [23]. Mutations in
gene encoding IDH were reported in various cancers including
glioma, glioblastoma multiforme, acute myeloid leukaemia, chon-
drosarcoma, and intrahepatic cholangiocarcinoma [40e42]. In
addition, IDH mutation has been reported to regulate a set of genes
 K. Sajnani et al. / Biochimie 135 (2017) 164e172
Fig. 2. Schematic representation of impacts of TCA cycle abnormalities in cancer. Impairment of Krebs cycle enzymes, metabolites and oncometabolites affects numerous
downstream metabolic pathways in cells which in turn promote carcinogenesis. Epigenetic and genetic alterations in TCA cycle components result in changing the cellular
behaviour towards the establishment of cancer.
at the transcriptional level, which are responsible for establishment
and progression of cancer [43]. Also, IDH mutations impair DNA
demethylation in gliomas and generate a hypermethylation
phenotype, which in turn was associated with the downregulation
of key genes implicated in differentiation of the chromafn cells
and the invasiveness of the paraganglioma [44].
The p53 gene plays crucial functions in multicellular organisms.
It prevents cancer formation, thus acts as a tumour suppressor
[45e47]. Genetic alteration of p53 is the most commonly studied
genetic alteration in cancer. The clinical and pathological roles of
p53 have been demonstrated in many cancers [48e51]. Yan and co-
worker reported that a substitution mutation at codon 132 of the
IDH gene was associated with the inactivation of p53 protein in
glioma [52]. Another study demonstrated that IDH mutation is an
early event in glioma, which in turn affects p53 protein function in
the later stage of patients with glioma [53].
PI3K/AKT and RAS proteins constitute important growth sig-
nalling pathways, which control the fate of cells. The pathway
mediated by these proteins is tightly regulated and controls pro-
grammed cell death, cell metabolism, proliferation and differenti-
ation [54]. Abnormalities of PI3K-Akt pathway regulation can lead
to an increase in signalling activity. This increased activation of
signalling has been linked to a range of diseases including cancer
[55]. It was demonstrated that IDH mutation activated the PI3K/
AKT signalling pathway in different cancers [56]. The authors also
noted that PI3K plays a signicant role in maintaining the glycolytic
phenotype of cancers through the protein kinase B (PKB/Akt) sig-
nalling network [56]. IDH mutation evokes hotspots in onco-
genes, such as KRAS [52]. Mutations in KRAS induce further
modication in the genome which promotes progression and
establishment of cancer [52].
Studies reported that IDH mutation produced a high level of
reactive oxygen species (ROS) in cancer cells [57,58]. ROS consist of
167
radical and non-radical oxygen species generated from a partial
reduction of oxygen and include, superoxide anion (O2-), hydrogen
peroxide (H2O2), hydrogen radicals and similar molecules [59].
These ROS induce oxidative stress in cells, which in turn stimulate
carcinogenesis [60].
Mutations in IDHs inhibit the generation of NADPH and were
also found to increase the consumption of NADPH by cells, which in
turn promote the production of (R)-2-hydroxyglutarate (2HG), an
oncometabolite [41,61]. It was noted that there was a correlation of
(R-)-2-hydroxyglutarate accumulation and tumorigenesis by
modulating the tumour suppressor phenomenon autophagy in
cells in an oxidizing [62].
Collagen is the key component of the extra-cellular matrix, the
network of bres that support the overall structure of tissues [63].
Collagen is also needed for the differentiation and proliferation of
neurons and haematopoietic stem cells in brain and bone marrow
[64]. Sasaki and colleagues noted that IDH mutation conferred
reduced prolyl hydroxylase domain activity, which in turn leads to
the disruption of collagen folding [65]. They also observed that this
activity contributed to progression of glioma and acute myeloid
leukaemia [66]. Therefore, mutations in IDH can affect different
biological processes that stimulate cancer formation and
progression.
4.4. Succinate dehydrogenase (SDH)
The succinate dehydrogenase complex (SDH) also called succi-
nate ubiquinones oxydoreductase is a hetero-tetrameric
(composed of SDHA, SDHB, SDHC and SDHD) and highly
conserved protein. SDHA and SDHB act as catalytic subunits and
SDHC and SDHD provide the binding site for ubiquinones (an
element of the electron transport chain) [67]. In the Krebs cycle,
SDH converts succinate to fumarate [23]. Mutation of genes
168 K. Sajnani et al. / Biochimie 135 (2017) 164e172
encoding proteins involved in the SDH complex leads to the accu-
mulation of succinate which can act as oncometabolite. Mutations
(loss of function) in SDH genes lead to hereditary paraganglioma
and phaeochromocytoma, and other hereditary syndromes and
cancers [67,68]. Mutation of SDH genes leads to an increase state of
intracellular ROS [69]. This ROS increase in turn induces metabolic
stress, genomic instability and promotes tumorigenesis [69].
Mutations in SDH have been observed to cause accumulation of
succinate in mitochondria which subsequently leaves mitochondria
and inhibits the activity of enzyme HIFa prolyl hydroxylases. This
inhibition permits escape of HIFa subunits from degradation and
allows them to bind to HIFb to form a heterodimer [70]. Under
hypoxic conditions, this heterodimer form an active complex which
acts on DNA sites of genes of interest. These genes in turn regulate
biological processes such as cell survival, angiogenesis, cell growth,
proliferation and glycolysis [71].
The HIF prolyl hydroxylases (PHDs) are central regulators for
molecular responses to oxygen availability [67]. PHD3 is an isoform
of PHD, and is expressed in response to hypoxia. This enzyme also
causes apoptosis in neural cells in oxygenated conditions [72]. It
was demonstrated that succinate accumulation leads to inactiva-
tion of the prolyl hydroxylase domain of PHD3. Inactivation of
PHD3 in turn reduces neuronal apoptosis [73]. It was also suggested
that failure in switching on apoptosis can contribute to the path-
ogenesis of phaeochromocytoma/paraganglioma [73].
G protein-coupled receptors, also called seven-transmembrane
domain receptors are the largest receptor family in humans and
are involved in a number of signal transduction pathways [74]. They
regulate various signalling pathways and play a crucial role in
different physiological processes as well as in tumour growth and
metastasis [67]. Elevated concentration of succinate modulates G
protein coupled metabolic receptor (GPR91) and stimulates the
release of VEGF (Vascular endothelial growth factor). This VEGF in
turn activates various subfamilies of growth factors and/or mito-
gens mediating kinase signalling pathways such as ERK1/2, JNK and
p38 MAPK etc. [75]. These pathways are involved in various bio-
logical processes responsible for proliferation, oncogenesis, angio-
genesis, apoptosis and cell cycle kinetics [76e78]. Thus, genetic
alteration in genes encoding the SDH complex leads to impaired
function of the enzyme complex and causes excess accumulation of
succinate. This accumulated succinate has the potential to trigger
cancer pathogenesis and progression.
4.5. Fumarate hydratase (FH)
Fumarate is produced from succinate by the enzyme avopro-
tein coupled succinate dehydrogenase [23]. Fumarate hydratase
(FH) converts fumarate to malate in the TCA cycle, an irreversible
reaction. Mutation in gene encoding FH leads to abnormal accu-
mulation of fumarate in cells [79]. This increased fumarate can act
as oncometabolite and promote cancer. FH mutation was rst re-
ported in the literature by Tomlinson and co-workers in renal cell
cancer and hereditary leiomyomatosis [80].
Reduced FH activity leads to HIFa stabilization. Stabilized HIFa
in FH mutant cells caused a metabolic shift to glycolysis from
oxidative phosphorylation [81]. Accumulated fumarate competi-
tively inhibits 2-oxoglutarate oxygenases, prolyl hydroxylase
domain and particularly the hypoxia inducible factor. These
competitive inhibitions produce hypoxia in the tissue microenvi-
ronment (actually they produce pseudohypoxia) and stabilize the
HIF complex. The HIF complex then potentially activates its onco-
genic targets and promotes cell growth and proliferation [82]. Also,
fumarate stimulates mRNA expression of HIF-1a through a non-
canonical NF-kB-dependent pathway [83].
FH mutation affects many proteins by the process of succination
at various amino residues [84]. Increased accumulation of succinate
facilitates the succination of protein residues. Succination is a post-
translational modication of proteins, in this process a succinyl
moiety (-CO-CH2-CH-2-CO-) is added to a lysine residue of the
protein molecule [85]. This posttranslational modication (adding
of succinyl unit to proteins) is noted in many proteins including
DNA binding histone proteins [85]. The potential impact of protein
succination is not clear yet, but it is assumed that it can induce
notable alteration in the structure and function of proteins. This is
because succination reverses the charge of lysine residues of pro-
teins (from 1 to 1) and also incorporates a bigger structural unit
(larger than acetylation or methylation) to the protein [86].
Fumarate acts as electrophile and interacts with cysteine residues
of target proteins to generate S-(2-succino) cysteine [67,87]. These
modied succinated proteins regulate various cellular responses
including activation of mitochondrial aconitase activity; inhibit
GAPDH (glyceraldehyde 3-phosphate dehydrogenase) activity,
activation of antioxidant pathway, and stimulation of the ROS sig-
nalling pathway [37,88]. These cellular responses in turn regulate
cell survival and proliferation [37,88].
Accumulated of fumarate due to mutation of FH reacts with
glutathione and produces the proto-oncometabolite, succinated
glutathione. Succinated glutathione is a novel cancer metabolite
and can mimic the glutathione substrate [88]. Therefore, it can react
with glutathione reductase [88]. As a result, it consumes NADPH
without the resultant antioxidant payoffs. Thus, FH impaired/de-
cient cells have decreased levels of NADPH; this favours production
of excessive levels of reactive oxygen species [88]. These ROS
further activate cancer metabolism in cells. Reduced FH activity
leads to HIFa stabilization. Stabilized HIFa in FH mutant cells
caused a metabolic shift to glycolysis from oxidative phosphoryla-
tion [89]. Thus, stabled HIFa could promote glycolysis in cancer
cells [89].
Glutaminolysis (lysis of glutamine), is a biochemical process in
which the amino acid glutamine is broken down to glutamate,
aspartate, carbon dioxide, pyruvate, lactate, alanine and citrate [23].
Glutamine which is present in higher concentration than other
amino acids serves as a major bio-energetic substrate and nitrogen
donor for cell proliferation [90]. Increase in glutaminolysis helps
cell growth in FH decient cells [91]. Thus the alteration of primary
metabolism in FH decient cells contributes towards further
oncogenic transformation. A detailed understanding of this inter-
relationship is not yet available and further research is needed [91].
Increased accumulation of fumarate promotes the succination of
Kelch-like ECH-associated protein 1, which in turn helps stabiliza-
tion the nuclear factor like 2 (NrF2) [92,93]. Accumulation of NrF2
leads to the activation of various antioxidant signalling pathways.
Thus, NrF2 helps FH mutant cells to tolerate high levels of oxidative
stress. This oxidative damage further promotes the pathogenesis of
cancer [91]. Thus, genetic alterations in the gene encoding FH
caused excess accumulation of fumarate which has the potential to
act as an oncometabolite. The increased concentration of fumarate
in cells allows HIF stabilization, switches on glycolysis, causes post-
translational modication of protein by succination, generates
succinated glutathione proto-oncometabolites and activates nu-
clear factors. These altered phenomena can activate different bio-
logical processes which in turn promote cancer pathogenesis.
5. Oncometabolites of the TCA cycle
Oncometabolites are small biomolecules (or enantiomers) of
normal metabolism. Excessive accumulation of them causes
metabolic dysregulation [91]. Consequently, cells with high onco-
metabolite concentrations undergo progression to cancer [91].
Oncometabolites of the TCA cycle are accumulated due to
 K. Sajnani et al. / Biochimie 135 (2017) 164e172 169

Table 1
Abnormalities of TCA cycle enzymes and metabolites in cancer.

Enzymes/TCA cycle product Altered Phenomena Cancer Type References

Mutated Enzymes
Actionase 2 Reduced expression Prostate carcinoma [39]
Loss of function Hereditary leiomyamtosis [37]
Renal cell carcinoma
Down regulation Gastric adenocarcinoma [38]
Isocitrate dehydrogenase Loss of heterozygosity and altered function Malignant glioma [41]
Point mutation and neomorphic function Leukaemia, Glioma [42]
Chondrosarcoma, intrahepatic cholangiocarcinoma
Loss of heterozygosity Glioblastoma [106]
Loss of heterozygosity Acute myeloid leukaemia [107]
Somatic mutation Glioblastoma [52]
Site specic mutation Biliary tract carcinoma and Cholongiocarcinoma [109]
Somatic mutations Colon cancer [116]
Missense somatic mutations Prostate carcinoma [117]
Missense somatic mutations Acute lymphoblastic leukaemia [117]
Succinate dehydrogenase Loss of function mutation Paraganglioma and Pheochromocytoma [67]
Germline mutations Renal carcinoma [118]
Germline mutations Gastrointestinal stromal tumour [119]
Low expression Breast cancer [120]
Fumarate hydratase Germline mutations Hereditary leiomyamtosis and renal cell carcinoma [80]
Heterozygous germline mutations Paraganglioma and Pheochromocytoma [44]
Chromosome deletion Neuroblastoma [121]
Reduced expression Clear cell carcinoma [89]
Downregulation Glioblastoma [122]
Oncometabolites
Citrate Synthase Loss of function Cervical carcinoma [33]
Overexpression Ovarian adenocarcinoma [34]
2-hydroxy glutarate Increased accumulation Leukaemia, [42]
Chondrosarcoma, Intrahepatic
Cholangiocarcinoma
Excess accumulation Chondroscaroma/chondroma [108]
Excess accumulation Biliary tract carcinoma and cholangiocarcinoma [109]

mutations of genes involved in metabolism. Fig. 2 shows different
oncometabolites of the TCA cycle and enzymes which lead to the
formation of these oncometabolites.
The oncometabolites can be divided in two categories - (I) native
oncometabolites that could be accumulated due to mutations (loss
of function) of genes encoding the enzymes, and (ii) promiscuous
oncometabolites that could be accumulated due to gain-of-function
mutations in metabolic enzymes [91]. Table 1 presents the abnor-
malities/altered phenomena of TCA-cycle enzymes and interme-
diate products associated with different cancers. The major
oncometabolites in cancer pathogenesis are discussed in the
following sections.
5.1. Citrate
Citrate accumulation in cancer environments will give rise to
epigenetic and non-epigenetic modications which could promote
the development and progression of cancer [94]. Excess citrate
reduces the activity of the mitochondrial isoform of pyruvate de-
hydrogenase and results in a shift of the cell's metabolism towards
glycolysis [94]. Increased accumulation of pyruvate leads cells to
convert pyruvate to lactate and regenerate NAD which is the key
factor for glycolysis [94] (Fig. 1). Thus citrate accumulation further
favours the non-oxidative breakdown of glucose in the cells and
promotes cancer growth.
Lipids are a class of bio-molecule with long hydrocarbon chains.
The main biological function of lipids includes storing energy, sig-
nalling and formation of membrane structure [95]. The key carbon
precursor for lipid synthesis is acetyl CoA [96]. Increased accumu-
lation of citrate activates the enzyme acetyl CoA carboxylase (ACC),
which in turn increases the production of acetyl CoA and malonyl
CoA [97,98]. This increased acetyl CoA and malonyl CoA is then
directed towards increased lipid/sterol synthesis [97,98]. The
transformed lipid metabolism observed in cancer cell shifts the
metabolic fate of lipid synthesis of the cell membrane and changes
the redox potential of cells. These alterations promote cellular
processes like cell growth, proliferation, cell survival signalling and
differentiation which in turn contributed in the tumorigenesis [99].
High energy demand is one of the characteristic features of
cancer cells [100]. Accumulated citrate in cancer cells stimulate
increased b oxidation of fatty acids and produced more energy, thus
providing sustaining energy for the cancer cells. This energy further
promotes proliferation of cancer cells [101].
Histones are the basic and principal proteins that regulate the
structural and functional organization of chromatin and also
regulate gene expressions [102]. These proteins undergo different
types of epigenetic and genetic modication. Acetylation of his-
tones emerges as a central regulator, which permits the inter-
conversion of permissive and repressive chromatin structure in
regards of transcriptional aptitudes [103]. Acetylation of histones is
signicantly controlled by several classes of enzymes such as his-
tone deacetylases and histones acetyltransferases. Both of these
enzymes regulate specic genes transcription by targeting specic
regions of the chromatin [101]. Excess acetyl CoA produced by
accumulated citrate encourages acetyl CoA dependent acetylation
of histone at N-terminal lysine residues [73,104,105]. Acetylation of
lysine residues modies the charge ratio of the protein, which
controls a numbers of proteins that are involved in cell metabolism,
cell kinetics, aging, angiogenesis, growth and development [73].
5.2. 2-Hydroxy glutarate (2HG)
Mutations of IDH1 and IDH2 (cytosolic and mitochondrial iso-
forms of IDH) lead to the accumulation of 2HG and acts as a
pathogenic metabolite (oncometabolite) in many cancers
[42,52,106e110]. Dang and co-workers demonstrated that a point
170 K. Sajnani et al. / Biochimie 135 (2017) 164e172
mutation (replacing arginine 132 with histidine) at the active site of
IDH1 (an isoform of IDH) was noted in primary glioma. They also
reported that this mutation was involved in the conversion of
alpha-ketuglutarates to R (-)-2-hydroxyglutarates (2HGs) [41].
Excessive accumulation of these 2HGs acts as an oncometabolite
and led to the malignant progression of gliomas [41] (Fig. 1).
DNA methylation in vertebrates acts as an epigenetic modi-
cation event [111]. DNA structure and histone methylation systems
are highly regulated and rely mechanistically on each other for
chromatin function [111]. Alterations in DNA methylation patterns,
such as hyper-methylation of CpG islands, are common changes
noted in human cancers [112]. Studies reported that increased
accumulated 2HG has potential tumorigenic activity and promotes
cancer growth by inhibiting the activity of DNA demethylases and
the ten-eleven translocation- 2 family of DNA demethylases
[113,114]. Another study also demonstrated that IDH mutations
block histone N-lysine demethylases jumonji domain containing
2A (JMJD2A) [114].
HIF, the major regulator of hypoxia is a heterodimer comprising
of alpha and b subunits [115]. Subunit a is degraded in presence of
oxygen by enzyme prolyl hydroxylases [19]. It was demonstrated
that 2HG stabilized HIF alpha by acting as a competitive inhibitor of
the prolyl hydroxylase enzyme [58].
6. Concluding remarks
Genetic alterations in the TCA cycle as well as the oncometa-
bolites generated are important in the pathogenesis of many can-
cers. From the growing body of knowledge on the subject, it is clear
that research in the eld of oncometabolite is a promising area for
scientists to develop targeted therapies for cancer. The exact
mechanisms of oncometabolites such as malate and oxaloacetate,
etc. leading to cancer are not clear. Therefore, investigation in this
eld in future will aid in improving our understanding of the role of
the TCA cycle enzymes and oncometabolites in the pathogenesis
and development of cancer.
Acknowledgements
The project was supported by the student scholarship from
Grifth University and funding from School of Medical Science and
Menzies Health Institute Queensland.
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