Mitochondrial dysfunctions in cancer: Genetic defects and oncogenic signaling impinging on TCA cycle activity

Cancer Letters xxx (2014) xxx–xxx

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Mitochondrial dysfunctions in cancer: Genetic defects and oncogenicsignaling impinging on TCA cycle activity

http://dx.doi.org/10.1016/j.canlet.2014.02.0230304-3835/� 2014 Elsevier Ireland Ltd. All rights reserved.

⇑ Corresponding author at: Department of Biology, University of Rome ‘‘TorVergata’’, Via della Ricerca Scientifica, 00133 Rome, Italy. Tel.: +39 06 7259 4369;fax: +39 06 7259 4311.

E-mail address: [email protected] (M.R. Ciriolo).

Please cite this article in press as: E. Desideri et al., Mitochondrial dysfunctions in cancer: Genetic defects and oncogenic signaling impinging on TCactivity, Cancer Lett. (2014), http://dx.doi.org/10.1016/j.canlet.2014.02.023

Enrico Desideri a, Rolando Vegliante a, Maria Rosa Ciriolo a,b,⇑a Department of Biology, University of Rome ‘‘Tor Vergata’’, Via della Ricerca Scientifica, 00133 Rome, Italyb IRCCS San Raffaele Pisana, Via di Val Cannuta, 00166 Rome, Italy

a r t i c l e i n f o

Article history:Received 20 December 2013Received in revised form 12 February 2014Accepted 18 February 2014Available online xxxx

Keywords:Isocitrate dehydrogenaseFumarate hydrataseSuccinate dehydrogenaseHIFp53Aconitase

a b s t r a c t

The tricarboxylic acid (TCA) cycle is a central route for oxidative metabolism. Besides being responsiblefor the production of NADH and FADH2, which fuel the mitochondrial electron transport chain to generateATP, the TCA cycle is also a robust source of metabolic intermediates required for anabolic reactions. Thisis particularly important for highly proliferating cells, like tumour cells, which require a continuoussupply of precursors for the synthesis of lipids, proteins and nucleic acids. A number of mutations amongthe TCA cycle enzymes have been discovered and their association with some tumour types has beenestablished. In this review we summarise the current knowledge regarding alterations of the TCA cyclein tumours, with particular attention to the three germline mutations of the enzymes succinate dehydro-genase, fumarate hydratase and isocitrate dehydrogenase, which are involved in the pathogenesis oftumours, and to the aberrant regulation of TCA cycle components that are under the control of oncogenesand tumour suppressors.

� 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Although mitochondria are often presented as power plantsproducing ATP by means of the oxidative phosphorylation(OXPHOS), this limited view does not reflect the importance ofthese organelles for cellular viability. Indeed, ATP production isonly one of the innumerable functions in which mitochondria areinvolved. For instance, they are responsible for the activation ofprogrammed mechanisms of cell death through the release ofpro-apoptotic molecules (e.g. cytochrome c and apoptosis-induc-ing factor) [1]. Mitochondria are also the organelles where theenzymes involved in the tricarboxylic acid (TCA) cycle reside. TheTCA cycle is pivotal for the entire cellular metabolism. Besidesproviding NADH and FADH2 required for the function of theelectron transport chain (ETC), many TCA cycle intermediates canbe converted and channeled towards anabolic pathways producinglipids, nucleic acids and proteins [2]. In the light of the essentialrole of mitochondria, it is not surprising that defects in mitochon-dria components have been found to be involved in the mostdiverse human diseases, ranging from neurodegeneration and

cardiovascular diseases to obesity and cancer [3–5]. In this review,we aim at summarising the current knowledge concerning therelationship linking defects and aberrant regulation of TCA cyclecomponents to tumour formation and progression.

2. Overview on the TCA cycle

In its most simplistic conception (Fig. 1), the TCA cycle (alsoknown as Kreb’s cycle or citric acid cycle) is a cyclic metabolicpathway consisting in the oxidation of acetyl-CoA, deriving fromglycolysis through pyruvate dehydrogenase and from lipid b-oxi-dation, to CO2, with the concomitant production of NADH andFADH2, which feed the ETC, and GTP/ATP. Namely, the net produc-tion is 3 NADH, 1 FADH2 and 1 GTP/ATP for each molecule of acet-yl-CoA consumed. The TCA cycle begins with the condensation ofthe acetyl moiety of acetyl-CoA with oxaloacetate by citrate syn-thase to form citrate. Citrate is reversibly isomerised to isocitrateby mitochondrial aconitase (ACO2) and then decarboxylated toa-ketoglutarate (a-KG) by mitochondrial isocitrate dehydrogenase(IDH). In this reaction, one molecule of CO2 is released and onemolecule of NAD+ is reduced to NADH. In the next step, a-KG isfurther decarboxylated to succinyl-CoA by a-KG dehydrogenase(a-KGDH) complex, with the release of a second molecule of CO2

and the production of a further molecule of NADH. The second partof the TCA cycle consists of a set of reactions aimed at oxidising

A cycle

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Fig. 1. Oncogenes and tumour suppressors tune the TCA cycle. TCA cycle alterations induced by oncogenes and tumour suppressors are shown. The tumour suppressor p53represses ACO2 expression and the TCA cycle-related enzyme ME1. HIF1-a upregulates PDK1 expression and indirectly downregulates ACO2. Myc upregulation replenishesTCA cycle by increasing GLS expression.

2 E. Desideri et al. / Cancer Letters xxx (2014) xxx–xxx

succinyl-CoA to restore oxaloacetate. Succinyl-CoA is transformedto succinate by succinate-CoA ligase (SUCL), also known assuccinate-CoA synthetase. SUCL is a dimeric protein consisting ofone a subunit (SUCL1) and one of b subunits, that can be eitherthe ADP-forming (SUCLA2) or the GDP-forming (SUCLG2); thenucleotide, ATP or GTP, generated in the reaction, depends on thetype of the b subunit present. Succinate is then oxidised to fuma-rate by succinate dehydrogenase (SDH), which also representsthe complex II of the ETC. In this step, a molecule of FADH2 isproduced. Then fumarate is hydrated to malate by fumarate hydra-tase (FH) and finally malate is oxidised by malate dehydrogenaseto restore oxaloacetate.

Besides being a central pathway for energetic metabolism, theTCA cycle provides metabolic intermediates for biosyntheticreactions (cataplerosis) leading to the de novo synthesis of pro-teins, lipids and nucleic acids. This property is particularlyexploited by fast-proliferating cells, such as tumour cells, whichrequire a continuous production of biomass to sustain their accel-erated growth rate. Citrate can be exported to the cytosol whereit is cleaved by ATP-citrate lyase (ACLY) to acetyl-CoA and oxalo-acetate. While acetyl-CoA is essential to sustain the de novo fattyacid synthesis, oxaloacetate can be converted to malate and thento pyruvate, with the concomitant production of NAD+ andNADPH, two essential cofactors for glycolysis and for the antiox-idant defense, respectively [6]. a-KG and oxaloacetate can beconverted into their related aminoacids, glutamate and aspartate,by glutamate dehydrogenase and aspartate aminotransferase, andthese amino acids can act as precursors for the synthesis of otheramino acids and for the de novo synthesis of purines. Finally, suc-cinyl-CoA is an intermediate in porphyrin and heme synthesis [7],whose increase is a hallmark of some tumour types, such ashuman breast carcinoma and non-small-cell lung cancer [8,9].

Please cite this article in press as: E. Desideri et al., Mitochondrial dysfunctionsactivity, Cancer Lett. (2014), http://dx.doi.org/10.1016/j.canlet.2014.02.023

Although many cancer cells rely primarily on glycolysis, ratherthan on OXPHOS to produce ATP [10–12], on the basis of whatis mentioned above the TCA cycle must be preserved to avoidthe depletion of its intermediates. In particular, differentreactions (anaplerosis) which refill and maintain the TCA cycleare induced to comply with this condition. Two of the mostimportant anaplerotic reactions are the ATP-dependent carboxyl-ation of pyruvate to oxaloacetate by pyruvate carboxylase, andthe conversion of glutamate, mainly deriving from the deamina-tion of glutamine by glutaminase 1, to a-KG by glutamatedehydrogenase [2,13].

3. Genetic defects in the TCA cycle are linked to canceroccurrence

Genetic defects have been found to affect TCA cycle componentsand to be responsible for the onset of a number of diseases, mainlythe neurodegenerative ones. Fumarate hydratase autosomicrecessive mutations cause severe and early encephalopathy [14].Patients with an inherited deficiency of a-KGDH present a progres-sive, severe encephalopathy with axial hypotonia and psychoticbehaviour [15], while mutations in the gene encoding for SUCLA2,have been found in patients affected by encephalomyopathy andmitochondrial DNA (mtDNA) depletion [16]. Despite the strongconnection between TCA cycle alterations and pathological condi-tions, the connection between tumourigenesis and cancer progres-sion remained elusive for long time. Indeed, only recently thedevelopment of some tumour types has been linked to dominantmutations of genes encoding for three TCA cycle enzymes, IDH,SDH and FH, paving the way for investigations about metabolicenzymes-mediated oncogenesis [17–19].

in cancer: Genetic defects and oncogenic signaling impinging on TCA cycle


E. Desideri et al. / Cancer Letters xxx (2014) xxx–xxx 3

3.1. Isocitrate dehydrogenase

There are three isoforms of IDH encoded by the nucleargenome: IDH1 and IDH2 are NADP+-dependent homodimericenzymes located in the cytosol and the mitochondria, respectively,whereas the NAD+-dependent IDH3 is a mitochondrial heterotetra-meric enzyme and the most active in the TCA cycle under physio-logical conditions [20]. While no correlation between IDH3mutations and cancer promotion has been documented so far[21], mutations in IDH1 and IDH2 were found in 70% of grade II–III gliomas and secondary glioblastomas [19,22], as well as in asmall fraction (about 16–17%) of acute myeloid leukemia patients[23]. Moreover, mutations in IDH1 and IDH2 are associated withtumours of other tissues such as thyroid and prostate, even if atlower frequencies [24,25]. The main IDH mutations identified insome of the described tumours are changes of the amino acidresidues R132 in IDH1 and R172 or R140 in IDH2 [26]. These muta-tions confer a neomorphic catalytic activity to the enzyme, consist-ing in the capability to convert a-KG into (R)-2-hydroxyglutaricacid ((R)-2HG), which has been demonstrated to be an oncometab-olite that drives the transformation of human astrocytes and theacquisition of a cancerous phenotype [26,27].

3.2. Succinate dehydrogenase

SDH is a nuclear genome–encoded enzyme made of foursubunits (named A–D) [28]. This is one of the few TCA cycleenzymes which does not have a cytosolic counterpart. The firstevidence of a connection between SDH mutations and cancerdevelopment emerged ten years ago when dominant mutationsin subunits SDHB, SDHC and SDHD were found in hereditary para-gangliomas and adrenal gland pheochromocytomas [29–31]. Morerecently, also mutations in SDHA have been associated with thesetumour types [32], and a link between mutations in SHDB andrenal cell carcinoma or T cell acute leukemia also exists[28,33,34]. Moreover, mutations in SDH genes correlate with thedevelopment of tumours of gastrointestinal, testicular and renaltissues [28]. Defects in the SDHB gene are mainly missense andnonsense mutations, while only nonsense mutations have beenfound in the SDHD gene [35].

3.3. Fumarate hydratase

The two FH isoforms encoded by the FH gene present a distinctsub-cellular localisation (i.e. cytosolic and mitochondrial) and bothfunction as homotetramers [36]. Dominant mutations in the FHgene, the majority of which are missense mutations, predisposeto tumour formation, whereas recessive mutations cause earlydeath and acute encephalopathies [18,37]. FH mutations areassociated with predisposition to multiple cutaneous and uterineleiomyomas, hereditary leiomyomatosis and renal cell cancer, withthe latter being particularly aggressive [18,38,39]. Other tumoursassociated with FH defects include Leydig cell tumours, ovary cys-tadenomas, cerebral cavernomas, uterine leiomyosarcomas andbreast cancer [40]. Patients with FH mutations show reduced mito-chondrial FH activity, and no detectable cytosolic enzyme suggest-ing that the tumour suppressor role of FH is associated with thecytoplasmic isoform [41].

4. Mechanisms linking TCA cycle genetic alterations and cancer

It is well established that mutations in the three TCA cycleenzymes described above cause several intracellular alterations,such as the accumulation of TCA cycle metabolites, which canfavour cancer occurrence. The most validated lines of evidence


show a direct link between TCA cycle defects, prolyl hydroxylases(PHDs) and cancer. Moreover, TCA cycle defects indirectly modu-late the intracellular redox state, which in turn may provide theoptimal environment for the formation and progression oftumours.

4.1. Prolyl hydroxylases, HIF1-a and the hypoxic response

Paragangliomas, developing in patients showing SDH defects,are frequent clinical presentations of people living at high altitudewho are exposed to a chronic hypoxic environment. This evidencesuggested a possible link between SDH mutations and the cellularpathways of hypoxic response [20]. Selak and colleagues were thefirst to demonstrate that SDH-deficient cells accumulate thehypoxic inducible factor 1 (HIF1, the main transcription factorregulating the hypoxic response [42]. It is well-known that thehypoxic response is a common hallmark of tumours since it pro-motes, for instance, metabolic adaptations (i.e. aerobic glycolysis)and angiogenesis [43]. These and other observations highlightedthe evidence that defects of TCA cycle enzymes are correlated tocancer by a mechanism that takes advantage of the hypoxic re-sponse. Under normoxia two proline residues in the a subunit ofHIF1 are hydroxylated by PHDs, a family of enzymes catalysingthe hydroxylation of a large class of substrates with the concomi-tant oxidation of a-KG to succinate. Once hydroxylated, HIF1-a isdegraded via the proteasome through a mechanism driven by theE3-ubiquitin ligase pVHL (encoded by the von Hippel-Lindaugene). Under hypoxic conditions or decreased a-KG levels, HIF-1a is no longer degraded, thereby accumulating in the nucleuswhere it can manage the hypoxic response via the transcriptionof a specific set of genes [44]. Pseudohypoxia is a very frequentcondition in tumour tissues, since cells adopt a hypoxic phenotypeeven in presence of normal oxygen tension. The notion that a-KGand succinate are involved in the reaction catalysed by PHDsclearly shows that the TCA cycle is strictly connected to the regu-lation of the hypoxic response. This evidence has been strength-ened by the demonstration that succinate, fumarate andoxalacetate can inhibit PHDs, resulting in the stabilisation ofHIF1-a and the activation of the downstream hypoxic pathways[45–48]. As a consequence, succinate and fumarate accumulation,due to SDH and FH deficiencies respectively, as well as decreaseda-KG availability resulting from the neomorphic activity of mu-tated IDH1 and IDH2, can all promote pseudohypoxia and supporttumour development and/or growth. So far, it is not yet clearwhether the pseudohypoxia response caused by TCA cycle defectsis sufficient to promote tumourigenesis or to support tumourprogression. However, some recent results are raising the questionwhether HIF1-a stabilisation can really represent a commonfeature of all tumour types deriving from TCA cycle defects. Indeed,Koivunen and coworkers demonstrated that HIF1-a acts assuppressor in tumours carrying IDH1/2 mutations as the oncome-tabolite (R)-2HG also promotes HIF1-a degradation by stabilisingPHDs activity [49]. Coherently, they also demonstrated that HIF1-a downregulation promoted the transformation and proliferationof astrocytes, thereby confirming a tumour suppressor role ofHIF1-a [49].

4.2. Prolyl hydroxylases and epigenetic regulation

PHDs are a large family of hydroxylases with broad-spectrumsubstrates. Therefore it is plausible that their reduced activity isassociated with tumourigenesis in a way independent of HIF1-aand pseudohypoxic phenotype [50]. For instance, in SDH mutants,succinate accumulation inhibits the activity of EglN3, a prolylhydroxylase necessary for the apoptotic cell death of some neuro-nal precursor cells occurring during development, thus potentially




facilitating carcinogenesis in these cells [51]. Another pseudohyp-oxia-independent mechanism linking the TCA cycle to tumoursinvolves epigenetic regulation that controls gene transcriptionalactivities through chemical modifications of DNA or histones. Forinstance, in IDH1/2-deficient models, increased levels of (R)-2HGinhibit the Ten-Eleven Translocation (TET) family of 5-methylcyto-sine (5mC) hydroxylases, which catalyse the a-KG-dependentremoval of methyl groups on DNA [52]. Interestingly, the accumu-lation of both fumarate and succinate can modulate gene expres-sion by inhibiting the activity of TETs, as well as that of thehistone demethylases Jumonji C-terminal domain, which deme-thylate substrates after having operated an a-KG-dependenthydroxylation [53–55].

4.3. Intracellular redox state

It has been known for many years that pro-oxidant conditions,in particular induced by mitochondria-deriving reactive oxygenspecies (ROS), can contribute to tumourigenesis or sustain tumourprogression. In fact, many tumour tissues show higher ROS levels,when compared to their normal counterparts [56]. A possible cor-relation between defects in the TCA cycle and pro-oxidant cellularenvironment can therefore be envisaged. It has been demonstratedthat IDH1/2-mutated cells are characterised by lower levels of glu-tamate with respect to normal cells, and this amino acid is requiredfor the biosynthesis of glutathione, the most abundant cellularantioxidant [57] that is involved in the regulation of many cellularprocesses [58,59]. Moreover, mutated IDHs not only have the en-zyme’s ability to produce NADPH impaired, but also contribute toNADPH consumption to generate (R)-2-HG [26,27]. Since NADPHis the main upstream electron donor for the maintenance of thewhole cellular antioxidant machinery, it is clear how IDH1/2 muta-tions can modulate the intracellular redox state towards a moreoxidising environment [60]. Oxidising conditions can trigger theactivation of autophagy [61], a tumour suppressor mechanism thatcould provide a possible link between (R)-2HG accumulation andtumourigenesis. Indeed, it has recently been demonstrated thatglioma cell lines expressing the R132H mutant of IDH1 show anaccumulation of the autophagic marker p62 [62], which is a hall-mark of defective autophagy and known to drive tumourigenesis[63]. Early studies in Caenorhabditis elegans show that SDHCmutant mev-1 generated superoxide O��2 [64,65] thereby indicatingthat ROS production can be also induced by SDH mutations. Fur-ther studies performed in mouse fibroblasts transfected with amurine equivalent of the mev-1 mutant confirmed that it inducesincreased ROS production and DNA mutation frequency [66].Conflicting data are, instead, available about the role of FH muta-tion-dependent fumarate accumulation in modulating the cellularredox state. The strongest evidence came from two separate stud-ies demonstrating that FH defects are associated with a reducedintracellular environment due to the activation of the nuclear fac-tor erythroid 2-related factor 2 (Nrf2), the main transcription fac-tor regulating the antioxidant defense [67,68]. Fumarateaccumulation results in succinylation of several cysteine residuesof Keap1, the inhibitory partner that physiologically preventsNrf2 nuclear translocation and activity, thereby resulting in thestabilization of Nrf2 [67,68]. The antioxidant response inducedupon FH mutation does not seem to reconcile with the assumptionthat pro-oxidant conditions favour tumours development. How-ever, it is worthwhile to remind that a highly reducing environ-ment also stimulates cell proliferation and preventsdifferentiation [69]. This aspect is particularly evident in cancerstem cells, in which the enhanced antioxidant defense and thereduced ROS levels with respect to their normal counterparts, in-crease the proliferation rate and likely promote the initial eventsunderlying cancer formation [70,71].


5. Beyond genetic defects: oncogenes and tumour suppressorscontrol TCA cycle activity

Genetic defects are not the sole alteration resulting in a dysreg-ulated TCA cycle. An aberrant expression of TCA cycle componentsmay represent either a direct or indirect consequence of oncogeneactivation or mutation of tumour suppressors (Fig. 1). HIF1-a andp53, two master regulators of cell metabolism that are oftenaltered in tumours, are good examples of proteins which have aprofound influence on TCA cycle functions.

5.1. Malic enzymes

The tumour suppressor p53 is mutated in a great number oftumour types [72,73]. It virtually influences all metabolic path-ways, including the TCA cycle. For instance, p53 can suppress theexpression of the TCA-related malic enzymes 1 (ME1) and 2(ME2), which convert malate into pyruvate and represent animportant source of NADPH [74]. The expression of MEs is aug-mented in some tumours, and their overexpression has beenshown to accelerate tumour growth in xenograft models [75,76].On the contrary, the downregulation of MEs reduces tumour cellgrowth through multiple mechanisms which include the stabiliza-tion of p53 and the induction of senescence [74]. The discovery ofthe mutual regulation of p53 and MEs provides the link betweenmetabolism and senescence and identifies MEs as new potentialtargets for the development of anticancer strategies.

5.2. Mitochondrial aconitase

A recently identified target of p53 in prostate cancer cells isACO2. Prostate cells produce and secrete great amounts of citrate.This is possible through a limiting ACO2 activity, which results in areduced conversion of citrate to isocitrate. The crucial role of ACO2in cancer is revealed by the evidence that an abnormal expressionof ACO2 is implicated in the tumourigenesis of prostate [77]. In2011, Tsui and colleagues revealed a possible rationale for theincreased expression of ACO2 mRNA in metastatic prostate cancercells. They discovered an inverse correlation between p53 expres-sion and ACO2 mRNA levels in human prostate carcinoma cells[78], albeit the molecular mechanism still remains unknown. Mul-tiple cancer-associated alterations that affect ACO2 expression oractivity are now emerging. In a very recent paper, Ternette et al.showed that FH-deficient cells present a decrease in ACO2 activity,resulting from the succination of three cysteine residues that arecrucial for the iron-sulphur cluster binding [79]. The repressionof ACO2 activity may contribute to the metabolic rearrangementobserved in many cancer cells and favour cancer development.The evidence that a decreased expression of ACO2 is associatedwith a poor prognosis in gastric cancer patients [80] is in agree-ment with this hypothesis. Further evidence supporting theinvolvement of ACO2 in tumours derives from the discovery thathypoxic conditions upregulate the HIF1-a target miR-210, bothin normal and transformed cells, and that miR-210 in turnrepresses the expression of iron-sulphur cluster assembly proteins.These proteins facilitate the assembly of iron-sulphur clustersincorporated into enzymes involved in mitochondrial metabolism,and their repression interferes with the enzymatic activity of manymitochondrial proteins, including ACO2 [81]. High expression lev-els of miR-210 are also associated with tumour proliferation andinvasion, and with a poor outcome in breast cancer patients [82].Decreased ACO2 expression results in higher levels of citrate,which can be redirected to the cytosol, thus contributing to restoreacetyl-CoA and oxaloacetate pools. Acetyl-CoA generated fromcitrate is required for the de novo synthesis of fatty acids, which




is elevated in many cancer cells to meet the high demand for sub-strates required for the production of biomass. The occurrence of alipogenic phenotype is increasingly considered as a new hallmarkof many cancer cells and is an appealing target for the develop-ment of novel anticancer therapies [83]. In this context, targetingcitrate metabolism has already revealed promising results in bothin vitro and in vivo studies. For instance, the inhibition of the citratecarrier restrains tumour proliferation in vitro and, similarly, theinhibition of ACLY, which converts citrate to acetyl-CoA and oxalo-acetate, impairs the growth and induces the differentiation ofmany glycolytic tumours [84,85]. Interestingly, a very recent find-ing revealed that ACLY inhibition reduced the population of cancerstem cells in many cell lines with a broad range of genetic back-grounds [86]. Although this work has been performed exclusivelyin vitro, the widespread applicability, together with the intriguingpossibility to target cancer stem cells, which are an underlyingcause of chemotherapy resistance and cancer recurrence [87],may provide new opportunities for the development of a highlyeffective therapy.

5.3. Pyruvate dehydrogenase kinase 1

The activation of HIF1-a is critical for the metabolic reprogram-ming of cancer cells, and usually results in the upregulation ofmany glycolytic enzymes and the repression of the activity of theTCA cycle [88]. One of the well documented effects of HIF1-aupregulation is the transactivation of the gene encoding for pyru-vate dehydrogenase kinase 1 (PDK1), which phosphorylates aserine residue on pyruvate dehydrogenase, thereby repressing itsactivity [89]. The overexpression of PDK1 is widespread in a largenumber of tumour types and is a key regulatory switch contribut-ing to the well-known glycolytic phenotype characteristic of manycancer and proliferating cells (the Warburg’s effect) [90,91].Indeed, PDK1 overexpression attenuates the flux of pyruvatethrough the TCA cycle and favours pyruvate conversion to lactateby lactate dehydrogenase to restore NAD+ required for glycolysis.Although the enhancement of glycolysis confers several metabolicadvantages to cancer cells, the reduction of pyruvate entry into theTCA cycle causes a depletion of TCA cycle intermediates, thuslimiting the availability of precursors for lipid, protein and nucleicacid synthesis. Therefore the TCA cycle must be maintained fullyfunctional and constantly replenished with its intermediates. Inthis context, the role of the oncogene Myc is crucial. Indeed, Mycregulates the expression of the enzyme glutaminase, which cataly-ses the first step of glutamine entry into the TCA cycle in the formof a-KG [92]. This key role of glutamine in maintaining a fully func-tional TCA cycle, in addition to its role as substrate for nucleic acid,glutathione and hexosamine synthesis, explains the extremeaddiction to glutamine exhibited by many cancer cells [93].

6. Concluding remarks

The TCA cycle represents the core of oxidative metabolism.Indeed, it is at the crossroads of two of the main metabolic routes,glycolysis and lipid b-oxidation. Alterations of TCA cycle compo-nents have long been known to correlate with the most diversepathologies, including neurodegeneration and cancer. Three germ-line dominant mutations of TCA cycle components (SDH, FH andIDH) have been discovered and associated with the pathogenesisof some tumours. Mutations of these enzymes result in theaccumulation of metabolites that activate HIF1-a (SDH and FH)or that are not present in normal conditions (IDH). Besides beinginvolved in tumourigenesis, alterations of TCA cycle componentscan be the result of oncogene activation (e.g. HIF1-a, Myc) ormutation of tumour suppressors (e.g. p53). In this scenario, ACO2


is a good example of an enzyme dysregulated in some types ofcancer and whose regulation is under the control of oncogenesand tumour suppressors, HIF1-a and p53, respectively. The advan-tage of ACO2 upregulation in cancer might be found in the accu-mulation of citrate, which can be exported to the cytosol andused as precursor for lipid and NADPH biosynthesis, molecules thatare required for tumour proliferation. Citrate export to the cytosolreveals a critical role of the TCA cycle in sustaining tumour growth.Indeed, despite many tumour cells preferentially use glycolysisinstead of OXPHOS for the production of ATP, the TCA cycleprovides many intermediates which are constantly drained by ana-bolic reactions. The impoverishment of the TCA cycle must there-fore be compensated by the continuous refill of its intermediatesthrough anaplerotic reactions. In the absence of sufficient replen-ishments, the TCA cycle would not work properly, resulting inthe inadequate supply of biomass for cancer cell growth. Thisaspect paves the way for therapeutic strategies targeting enzymesinvolved in anaplerotic reactions, which could exploit the extremeaddiction of cancer cells to biosynthetic precursors, in the absenceof which the proliferation rate and the viability will be stronglycompromised.

Acknowledgments

This work was partially supported by Grants from AssociazioneItaliana per la Ricerca sul Cancro (AIRC, IG 10636) and Ministerodell’Istruzione, dell’Università e della Ricerca (MIUR).

References

[1] C. Wang, R.J. Youle, The role of mitochondria in apoptosis*, Annu. Rev. Genet.43 (2009) 95–118.

[2] O.E. Owen, S.C. Kalhan, R.W. Hanson, The key role of anaplerosis andcataplerosis for citric acid cycle function, J. Biol. Chem. 277 (2002) 30409–30412.

[3] J. Nunnari, A. Suomalainen, Mitochondria: in sickness and in health, Cell 148(2012) 1145–1159.

[4] M. Brandon, P. Baldi, D.C. Wallace, Mitochondrial mutations in cancer,Oncogene 25 (2006) 4647–4662.

[5] J.C. Bournat, C.W. Brown, Mitochondrial dysfunction in obesity, Curr. Opin.Endocrinol. Diabetes Obesity 17 (2010) 446–452.

[6] D.C. Wallace, W. Fan, V. Procaccio, Mitochondrial energetics and therapeutics,Annu. Rev. Pathol. 5 (2010) 297–348.

[7] R.F. Labbe, T. Kurumada, J. Onisawa, The role of succinyl-CoA synthetase in thecontrol of heme biosynthesis, Biochim. Biophys. Acta 111 (1965) 403–415.

[8] J. Hooda, D. Cadinu, M.M. Alam, A. Shah, T.M. Cao, L.A. Sullivan, R. Brekken, L.Zhang, Enhanced heme function and mitochondrial respiration promote theprogression of lung cancer cells, PLoS ONE 8 (2013) e63402.

[9] N.M. Navone, C.F. Polo, A.L. Frisardi, N.E. Andrade, A.M. Battle, Hemebiosynthesis in human breast cancer–mimetic ‘‘in vitro’’ studies and someheme enzymic activity levels, Int. J. Biochem. 22 (1990) 1407–1411.

[10] J. Zheng, Energy metabolism of cancer: glycolysis versus oxidativephosphorylation (review), Oncol. Lett. 4 (2012) 1151–1157.

[11] D.A. Scott, A.D. Richardson, F.V. Filipp, C.A. Knutzen, G.G. Chiang, Z.A. Ronai,A.L. Osterman, J.W. Smith, Comparative metabolic flux profiling of melanomacell lines: beyond the Warburg effect, J. Biol. Chem. 286 (2011) 42626–42634.

[12] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144(2011) 646–674.

[13] S. Jitrapakdee, A. Vidal-Puig, J.C. Wallace, Anaplerotic roles of pyruvatecarboxylase in mammalian tissues, Cell. Mol. Life Sci. 63 (2006) 843–854.

[14] A.G. Saini, P. Singhi, Infantile metabolic encephalopathy due to fumarasedeficiency, J. Child Neurol. 28 (2013) 535–537.

[15] N. Guffon, C. Lopez-Mediavilla, R. Dumoulin, B. Mousson, C. Godinot, H. Carrier,J.M. Collombet, P. Divry, M. Mathieu, P. Guibaud, 2-Ketoglutaratedehydrogenase deficiency, a rare cause of primary hyperlactataemia: reportof a new case, J. Inherit. Metab. Dis. 16 (1993) 821–830.

[16] R. Carrozzo, C. Dionisi-Vici, U. Steuerwald, S. Lucioli, F. Deodato, S. DiGiandomenico, E. Bertini, B. Franke, L.A. Kluijtmans, M.C. Meschini, C. Rizzo,F. Piemonte, R. Rodenburg, R. Santer, F.M. Santorelli, A. van Rooij, D. Vermunt-de Koning, E. Morava, R.A. Wevers, SUCLA2 mutations are associated with mildmethylmalonic aciduria, Leigh-like encephalomyopathy, dystonia anddeafness, Brain 130 (2007) 862–874.

[17] B.E. Baysal, R.E. Ferrell, J.E. Willett-Brozick, E.C. Lawrence, D. Myssiorek, A.Bosch, A. van der Mey, P.E. Taschner, W.S. Rubinstein, E.N. Myers, C.W. Richard3rd, C.J. Cornelisse, P. Devilee, B. Devlin, Mutations in SDHD, a mitochondrialcomplex II gene, in hereditary paraganglioma, Science 287 (2000) 848–851.


http://refhub.elsevier.com/S0304-3835(14)00130-X/h0005

















































[18] I.P. Tomlinson, N.A. Alam, A.J. Rowan, E. Barclay, E.E. Jaeger, D. Kelsell, I. Leigh,P. Gorman, H. Lamlum, S. Rahman, R.R. Roylance, S. Olpin, S. Bevan, K. Barker,N. Hearle, R.S. Houlston, M. Kiuru, R. Lehtonen, A. Karhu, S. Vilkki, P. Laiho, C.Eklund, O. Vierimaa, K. Aittomaki, M. Hietala, P. Sistonen, A. Paetau, R.Salovaara, R. Herva, V. Launonen, L.A. Aaltonen, Germline mutations in FHpredispose to dominantly inherited uterine fibroids, skin leiomyomata andpapillary renal cell cancer, Nat. Genet. 30 (2002) 406–410.

[19] H. Yan, D.W. Parsons, G. Jin, R. McLendon, B.A. Rasheed, W. Yuan, I. Kos, I.Batinic-Haberle, S. Jones, G.J. Riggins, H. Friedman, A. Friedman, D. Reardon, J.Herndon, K.W. Kinzler, V.E. Velculescu, B. Vogelstein, D.D. Bigner, IDH1 andIDH2 mutations in gliomas, N. Engl. J. Med. 360 (2009) 765–773.

[20] N. Raimundo, B.E. Baysal, G.S. Shadel, Revisiting the TCA cycle: signaling totumor formation, Trends Mol. Med. 17 (2011) 641–649.

[21] D. Krell, M. Assoku, M. Galloway, P. Mulholland, I. Tomlinson, C. Bardella,Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations inglioblastoma, PLoS ONE 6 (2011) e19868.

[22] D.W. Parsons, S. Jones, X. Zhang, J.C. Lin, R.J. Leary, P. Angenendt, P. Mankoo, H.Carter, I.M. Siu, G.L. Gallia, A. Olivi, R. McLendon, B.A. Rasheed, S. Keir, T.Nikolskaya, Y. Nikolsky, D.A. Busam, H. Tekleab, L.A. Diaz Jr., J. Hartigan, D.R.Smith, R.L. Strausberg, S.K. Marie, S.M. Shinjo, H. Yan, G.J. Riggins, D.D. Bigner,R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein, V.E. Velculescu, K.W.Kinzler, An integrated genomic analysis of human glioblastoma multiforme,Science 321 (2008) 1807–1812.

[23] L. Dang, S. Jin, S.M. Su, IDH mutations in glioma and acute myeloid leukemia,Trends Mol. Med. 16 (2010) 387–397.

[24] M.R. Kang, M.S. Kim, J.E. Oh, Y.R. Kim, S.Y. Song, S.I. Seo, J.Y. Lee, N.J. Yoo, S.H.Lee, Mutational analysis of IDH1 codon 132 in glioblastomas and othercommon cancers, Int. J. Cancer 125 (2009) 353–355.

[25] K.E. Yen, M.A. Bittinger, S.M. Su, V.R. Fantin, Cancer-associated IDH mutations:biomarker and therapeutic opportunities, Oncogene 29 (2010) 6409–6417.

[26] L. Dang, D.W. White, S. Gross, B.D. Bennett, M.A. Bittinger, E.M. Driggers, V.R.Fantin, H.G. Jang, S. Jin, M.C. Keenan, K.M. Marks, R.M. Prins, P.S. Ward, K.E.Yen, L.M. Liau, J.D. Rabinowitz, L.C. Cantley, C.B. Thompson, M.G. VanderHeiden, S.M. Su, Cancer-associated IDH1 mutations produce 2-hydroxyglutarate, Nature 462 (2009) 739–744.

[27] P.S. Ward, J. Patel, D.R. Wise, O. Abdel-Wahab, B.D. Bennett, H.A. Coller, J.R.Cross, V.R. Fantin, C.V. Hedvat, A.E. Perl, J.D. Rabinowitz, M. Carroll, S.M. Su,K.A. Sharp, R.L. Levine, C.B. Thompson, The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activityconverting alpha-ketoglutarate to 2-hydroxyglutarate, Cancer Cell 17 (2010)225–234.

[28] C. Bardella, P.J. Pollard, I. Tomlinson, SDH mutations in cancer, Biochim.Biophys. Acta 2011 (1807) 1432–1443.

[29] S. Niemann, U. Muller, Mutations in SDHC cause autosomal dominantparaganglioma, type 3, Nat. Genet. 26 (2000) 268–270.

[30] D. Astuti, F. Douglas, T.W. Lennard, I.A. Aligianis, E.R. Woodward, D.G. Evans, C.Eng, F. Latif, E.R. Maher, Germline SDHD mutation in familialphaeochromocytoma, Lancet 357 (2001) 1181–1182.

[31] B.E. Baysal, J.E. Willett-Brozick, E.C. Lawrence, C.M. Drovdlic, S.A. Savul, D.R.McLeod, H.A. Yee, D.E. Brackmann, W.H. Slattery 3rd, E.N. Myers, R.E. Ferrell,W.S. Rubinstein, Prevalence of SDHB, SDHC, and SDHD germline mutations inclinic patients with head and neck paragangliomas, J. Med. Genet. 39 (2002)178–183.

[32] N. Burnichon, J.J. Briere, R. Libe, L. Vescovo, J. Riviere, F. Tissier, E. Jouanno, X.Jeunemaitre, P. Benit, A. Tzagoloff, P. Rustin, J. Bertherat, J. Favier, A.P.Gimenez-Roqueplo, SDHA is a tumor suppressor gene causing paraganglioma,Hum. Mol. Genet. 19 (2010) 3011–3020.

[33] S. Vanharanta, M. Buchta, S.R. McWhinney, S.K. Virta, M. Peczkowska, C.D.Morrison, R. Lehtonen, A. Januszewicz, H. Jarvinen, M. Juhola, J.P. Mecklin, E.Pukkala, R. Herva, M. Kiuru, N.N. Nupponen, L.A. Aaltonen, H.P. Neumann, C.Eng, Early-onset renal cell carcinoma as a novel extraparaganglial componentof SDHB-associated heritable paraganglioma, Am. J. Hum. Genet. 74 (2004)153–159.

[34] B.E. Baysal, A recurrent stop-codon mutation in succinate dehydrogenasesubunit B gene in normal peripheral blood and childhood T-cell acuteleukemia, PLoS ONE 2 (2007) e436.

[35] E. Gottlieb, I.P. Tomlinson, Mitochondrial tumour suppressors: a genetic andbiochemical update, Nat. Rev. Cancer 5 (2005) 857–866.

[36] I.E. Scheffler, Mitochondria, second ed., J. Wiley and Sons Inc, Hoboken, NewJersey, 2008.

[37] J.P. Bayley, V. Launonen, I.P. Tomlinson, The FH mutation database: an onlinedatabase of fumarate hydratase mutations involved in the MCUL (HLRCC)tumor syndrome and congenital fumarase deficiency, BMC Med. Genet. 9(2008) 20.

[38] V. Launonen, O. Vierimaa, M. Kiuru, J. Isola, S. Roth, E. Pukkala, P. Sistonen, R.Herva, L.A. Aaltonen, Inherited susceptibility to uterine leiomyomas and renalcell cancer, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 3387–3392.

[39] M.A. Refae, N. Wong, F. Patenaude, L.R. Begin, W.D. Foulkes, Hereditaryleiomyomatosis and renal cell cancer: an unusual and aggressive form ofhereditary renal carcinoma, Nat. Clin. Pract. Oncol. 4 (2007) 256–261.

[40] H.J. Lehtonen, Hereditary leiomyomatosis and renal cell cancer: update onclinical and molecular characteristics, Familial Cancer 10 (2011) 397–411.

[41] N. Raimundo, J. Ahtinen, K. Fumic, I. Baric, A.M. Remes, R. Renkonen, R. Lapatto,A. Suomalainen, Differential metabolic consequences of fumarate hydrataseand respiratory chain defects, Biochim. Biophys. Acta 1782 (2008) 287–294.


[42] M.A. Selak, S.M. Armour, E.D. MacKenzie, H. Boulahbel, D.G. Watson, K.D.Mansfield, Y. Pan, M.C. Simon, C.B. Thompson, E. Gottlieb, Succinate links TCAcycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase,Cancer Cell 7 (2005) 77–85.

[43] A.J. Majmundar, W.J. Wong, M.C. Simon, Hypoxia-inducible factors and theresponse to hypoxic stress, Mol. Cell 40 (2010) 294–309.

[44] K. Tanimoto, Y. Makino, T. Pereira, L. Poellinger, Mechanism of regulation ofthe hypoxia-inducible factor-1 alpha by the von Hippel–Lindau tumorsuppressor protein, EMBO J. 19 (2000) 4298–4309.

[45] L. O’Flaherty, J. Adam, L.C. Heather, A.V. Zhdanov, Y.L. Chung, M.X. Miranda, J.Croft, S. Olpin, K. Clarke, C.W. Pugh, J. Griffiths, D. Papkovsky, H. Ashrafian, P.J.Ratcliffe, P.J. Pollard, Dysregulation of hypoxia pathways in fumaratehydratase-deficient cells is independent of defective mitochondrialmetabolism, Hum. Mol. Genet. 19 (2010) 3844–3851.

[46] O. Yogev, E. Singer, E. Shaulian, M. Goldberg, T.D. Fox, O. Pines, Fumarase: amitochondrial metabolic enzyme and a cytosolic/nuclear component of theDNA damage response, PLoS Biol. 8 (2010) e1000328.

[47] J.S. Isaacs, Y.J. Jung, D.R. Mole, S. Lee, C. Torres-Cabala, Y.L. Chung, M. Merino, J.Trepel, B. Zbar, J. Toro, P.J. Ratcliffe, W.M. Linehan, L. Neckers, HIFoverexpression correlates with biallelic loss of fumarate hydratase in renalcancer: novel role of fumarate in regulation of HIF stability, Cancer Cell 8(2005) 143–153.

[48] P. Koivunen, M. Hirsila, A.M. Remes, I.E. Hassinen, K.I. Kivirikko, J. Myllyharju,Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycleintermediates: possible links between cell metabolism and stabilization of HIF,J. Biol. Chem. 282 (2007) 4524–4532.

[49] P. Koivunen, S. Lee, C.G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J.A. Losman, P.Joensuu, U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K.L. Ligon, R.G.Verhaak, H. Yan, W.G. Kaelin Jr., Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation, Nature 483 (2012) 484–488.

[50] A. Ozer, R.K. Bruick, Non-heme dioxygenases: cellular sensors and regulatorsjelly rolled into one?, Nat Chem. Biol. 3 (2007) 144–153.

[51] S. Lee, E. Nakamura, H. Yang, W. Wei, M.S. Linggi, M.P. Sajan, R.V. Farese, R.S.Freeman, B.D. Carter, W.G. Kaelin Jr., S. Schlisio, Neuronal apoptosis linked toEglN3 prolyl hydroxylase and familial pheochromocytoma genes:developmental culling and cancer, Cancer Cell 8 (2005) 155–167.

[52] M.E. Figueroa, O. Abdel-Wahab, C. Lu, P.S. Ward, J. Patel, A. Shih, Y. Li, N.Bhagwat, A. Vasanthakumar, H.F. Fernandez, M.S. Tallman, Z. Sun, K. Wolniak,J.K. Peeters, W. Liu, S.E. Choe, V.R. Fantin, E. Paietta, B. Lowenberg, J.D. Licht,L.A. Godley, R. Delwel, P.J. Valk, C.B. Thompson, R.L. Levine, A. Melnick,Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype,disrupt TET2 function, and impair hematopoietic differentiation, Cancer Cell18 (2010) 553–567.

[53] A.M. Cervera, J.P. Bayley, P. Devilee, K.J. McCreath, Inhibition of succinatedehydrogenase dysregulates histone modification in mammalian cells, Mol.Cancer 8 (2009) 89.

[54] E.H. Smith, R. Janknecht, L.J. Maher 3rd, Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma, Hum.Mol. Genet. 16 (2007) 3136–3148.

[55] M. Xiao, H. Yang, W. Xu, S. Ma, H. Lin, H. Zhu, L. Liu, Y. Liu, C. Yang, Y. Xu, S.Zhao, D. Ye, Y. Xiong, K.L. Guan, Inhibition of alpha-KG-dependent histone andDNA demethylases by fumarate and succinate that are accumulated inmutations of FH and SDH tumor suppressors, Genes Dev. 26 (2012) 1326–1338.

[56] S. Toyokuni, K. Okamoto, J. Yodoi, H. Hiai, Persistent oxidative stress in cancer,FEBS Lett. 358 (1995) 1–3.

[57] Z.J. Reitman, G. Jin, E.D. Karoly, I. Spasojevic, J. Yang, K.W. Kinzler, Y. He, D.D.Bigner, B. Vogelstein, H. Yan, Profiling the effects of isocitrate dehydrogenase 1and 2 mutations on the cellular metabolome, Proc. Natl. Acad. Sci. U. S. A. 108(2011) 3270–3275.

[58] R. Franco, J.A. Cidlowski, Apoptosis and glutathione: beyond an antioxidant,Cell Death Differ. 16 (2009) 1303–1314.

[59] E. Desideri, G. Filomeni, M.R. Ciriolo, Glutathione participates in themodulation of starvation-induced autophagy in carcinoma cells, Autophagy8 (2012) 1769–1781.

[60] G. Filomeni, G. Rotilio, M.R. Ciriolo, Disulfide relays and phosphorylativecascades: partners in redox-mediated signaling pathways, Cell Death Differ. 12(2005) 1555–1563.

[61] G. Filomeni, E. Desideri, S. Cardaci, G. Rotilio, M.R. Ciriolo, Under the ROS...thiolnetwork is the principal suspect for autophagy commitment, Autophagy 6(2010) 999–1005.

[62] M.R. Gilbert, Y. Liu, J. Neltner, H. Pu, A. Morris, M. Sunkara, T. Pittman, N.Kyprianou, C. Horbinski, Autophagy and oxidative stress in gliomas with IDH1mutations, Acta Neuropathol. (Berl.) (2013).

[63] R. Mathew, C.M. Karp, B. Beaudoin, N. Vuong, G. Chen, H.Y. Chen, K. Bray, A.Reddy, G. Bhanot, C. Gelinas, R.S. Dipaola, V. Karantza-Wadsworth, E. White,Autophagy suppresses tumorigenesis through elimination of p62, Cell 137(2009) 1062–1075.

[64] N. Ishii, M. Fujii, P.S. Hartman, M. Tsuda, K. Yasuda, N. Senoo-Matsuda, S.Yanase, D. Ayusawa, K. Suzuki, A mutation in succinate dehydrogenasecytochrome b causes oxidative stress and ageing in nematodes, Nature 394(1998) 694–697.

[65] N. Senoo-Matsuda, K. Yasuda, M. Tsuda, T. Ohkubo, S. Yoshimura, H.Nakazawa, P.S. Hartman, N. Ishii, A defect in the cytochrome b large subunitin complex II causes both superoxide anion overproduction and abnormal















































































































































































energy metabolism in caenorhabditis elegans, J. Biol. Chem. 276 (2001)41553–41558.

[66] T. Ishii, K. Yasuda, A. Akatsuka, O. Hino, P.S. Hartman, N. Ishii, A mutation inthe SDHC gene of complex II increases oxidative stress, resulting in apoptosisand tumorigenesis, Cancer Res. 65 (2005) 203–209.

[67] J. Adam, E. Hatipoglu, L. O’Flaherty, N. Ternette, N. Sahgal, H. Lockstone, D.Baban, E. Nye, G.W. Stamp, K. Wolhuter, M. Stevens, R. Fischer, P. Carmeliet,P.H. Maxwell, C.W. Pugh, N. Frizzell, T. Soga, B.M. Kessler, M. El-Bahrawy, P.J.Ratcliffe, P.J. Pollard, Renal cyst formation in Fh1-deficient mice is independentof the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2signaling, Cancer Cell 20 (2011) 524–537.

[68] A. Ooi, J.C. Wong, D. Petillo, D. Roossien, V. Perrier-Trudova, D. Whitten, B.W.Min, M.H. Tan, Z. Zhang, X.J. Yang, M. Zhou, B. Gardie, V. Molinie, S. Richard,P.H. Tan, B.T. Teh, K.A. Furge, An antioxidant response phenotype sharedbetween hereditary and sporadic type 2 papillary renal cell carcinoma, CancerCell 20 (2011) 511–523.

[69] F.Q. Schafer, G.R. Buettner, Redox environment of the cell as viewed throughthe redox state of the glutathione disulfide/glutathione couple, Free RadicalBiol. Med. 30 (2001) 1191–1212.

[70] M. Diehn, R.W. Cho, N.A. Lobo, T. Kalisky, M.J. Dorie, A.N. Kulp, D. Qian, J.S. Lam,L.E. Ailles, M. Wong, B. Joshua, M.J. Kaplan, I. Wapnir, F.M. Dirbas, G. Somlo, C.Garberoglio, B. Paz, J. Shen, S.K. Lau, S.R. Quake, J.M. Brown, I.L. Weissman, M.F.Clarke, Association of reactive oxygen species levels and radioresistance incancer stem cells, Nature 458 (2009) 780–783.

[71] T. Ishimoto, O. Nagano, T. Yae, M. Tamada, T. Motohara, H. Oshima, M. Oshima,T. Ikeda, R. Asaba, H. Yagi, T. Masuko, T. Shimizu, T. Ishikawa, K. Kai, E.Takahashi, Y. Imamura, Y. Baba, M. Ohmura, M. Suematsu, H. Baba, H. Saya,CD44 variant regulates redox status in cancer cells by stabilizing the xCTsubunit of system xc(-) and thereby promotes tumor growth, Cancer cell 19(2011) 387–400.

[72] M. Olivier, M. Hollstein, P. Hainaut, TP53 mutations in human cancers: origins,consequences, and clinical use, Cold Spring Harb. Perspect. Biol. 2 (2010)a001008.

[73] P.A. Muller, K.H. Vousden, P53 mutations in cancer, Nat. Cell Biol. 15 (2013) 2–8.

[74] P. Jiang, W. Du, A. Mancuso, K.E. Wellen, X. Yang, Reciprocal regulation of p53and malic enzymes modulates metabolism and senescence, Nature 493 (2013)689–693.

[75] W.J. Wasilenko, A.C. Marchok, Malic enzyme and malate dehydrogenaseactivities in rat tracheal epithelial cells during the progression of neoplasia,Cancer Lett. 28 (1985) 35–42.

[76] L.A. Sauer, R.T. Dauchy, W.O. Nagel, H.P. Morris, Mitochondrial malic enzymes.Mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas,J. Biol. Chem. 255 (1980) 3844–3848.

[77] K.K. Singh, M.M. Desouki, R.B. Franklin, L.C. Costello, Mitochondrial aconitaseand citrate metabolism in malignant and nonmalignant human prostatetissues, Mol. Cancer 5 (2006) 14.

[78] K.H. Tsui, T.H. Feng, Y.F. Lin, P.L. Chang, H.H. Juang, P53 downregulates thegene expression of mitochondrial aconitase in human prostate carcinomacells, Prostate 71 (2011) 62–70.


[79] N. Ternette, M. Yang, M. Laroyia, M. Kitagawa, L. O’Flaherty, K. Wolhulter, K.Igarashi, K. Saito, K. Kato, R. Fischer, A. Berquand, B.M. Kessler, T. Lappin, N.Frizzell, T. Soga, J. Adam, P.J. Pollard, Inhibition of mitochondrial aconitase bysuccination in fumarate hydratase deficiency, Cell Rep. 3 (2013) 689–700.

[80] P. Wang, C. Mai, Y.L. Wei, J.J. Zhao, Y.M. Hu, Z.L. Zeng, J. Yang, W.H. Lu, R.H. Xu,P. Huang, Decreased expression of the mitochondrial metabolic enzymeaconitase (ACO2) is associated with poor prognosis in gastric cancer, Med.Oncol. 30 (2013) 552.

[81] S.Y. Chan, Y.Y. Zhang, C. Hemann, C.E. Mahoney, J.L. Zweier, J. Loscalzo,MicroRNA-210 controls mitochondrial metabolism during hypoxia byrepressing the iron–sulfur cluster assembly proteins ISCU1/2, Cell Metab. 10(2009) 273–284.

[82] F. Rothe, M. Ignatiadis, C. Chaboteaux, B. Haibe-Kains, N. Kheddoumi, S. Majjaj,B. Badran, H. Fayyad-Kazan, C. Desmedt, A.L. Harris, M. Piccart, C. Sotiriou,Global microRNA expression profiling identifies MiR-210 associated withtumor proliferation, invasion and poor clinical outcome in breast cancer, PLoSONE 6 (2011) e20980.

[83] C.R. Santos, A. Schulze, Lipid metabolism in cancer, FEBS J. 279 (2012) 2610–2623.

[84] G. Hatzivassiliou, F. Zhao, D.E. Bauer, C. Andreadis, A.N. Shaw, D. Dhanak, S.R.Hingorani, D.A. Tuveson, C.B. Thompson, ATP citrate lyase inhibition cansuppress tumor cell growth, Cancer Cell 8 (2005) 311–321.

[85] O. Catalina-Rodriguez, V.K. Kolukula, Y. Tomita, A. Preet, F. Palmieri, A.Wellstein, S. Byers, A.J. Giaccia, E. Glasgow, C. Albanese, M.L. Avantaggiati, Themitochondrial citrate transporter, CIC, is essential for mitochondrialhomeostasis, Oncotarget 3 (2012) 1220–1235.

[86] J.I. Hanai, N. Doro, P. Seth, V.P. Sukhatme, ATP citrate lyase knockdown impactscancer stem cells in vitro, Cell Death Dis. 4 (2013) e696.

[87] X. Ning, J. Shu, Y. Du, Q. Ben, Z. Li, Therapeutic strategies targeting cancer stemcells, Cancer Biol. Ther. 14 (2013) 295–303.

[88] J. Pouyssegur, F. Dayan, N.M. Mazure, Hypoxia signalling in cancer andapproaches to enforce tumour regression, Nature 441 (2006) 437–443.

[89] J.W. Kim, I. Tchernyshyov, G.L. Semenza, C.V. Dang, HIF-1-mediated expressionof pyruvate dehydrogenase kinase: a metabolic switch required for cellularadaptation to hypoxia, Cell Metab. 3 (2006) 177–185.

[90] S. Fujiwara, Y. Kawano, H. Yuki, Y. Okuno, K. Nosaka, H. Mitsuya, H. Hata, PDK1inhibition is a novel therapeutic target in multiple myeloma, Br. J. Cancer 108(2013) 170–178.

[91] R.A. Cairns, I.S. Harris, T.W. Mak, Regulation of cancer cell metabolism, Nat.Rev. Cancer 11 (2011) 85–95.

[92] P. Gao, I. Tchernyshyov, T.C. Chang, Y.S. Lee, K. Kita, T. Ochi, K.I. Zeller, A.M. DeMarzo, J.E. Van Eyk, J.T. Mendell, C.V. Dang, c-Myc suppression of miR-23a/benhances mitochondrial glutaminase expression and glutamine metabolism,Nature 458 (2009) 762–765.

[93] D.R. Wise, C.B. Thompson, Glutamine addiction: a new therapeutic target incancer, Trends Biochem. Sci. 35 (2010) 427–433.




































































































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Mitochondrial dysfunctions in cancer: Genetic defects and oncogenic signaling impinging on TCA cycle activity