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Am J Physiol Cell Physiol 291: C1114 –C1120, 2006.
First published June 7, 2006; doi:10.1152/ajpcell.00216.2006.
Invited Review
Tricarboxylic acid cycle dysfunction as a cause of
human diseases and tumor formation
Jean-Jacques Brière,1 Judith Favier,2 Anne-Paule Gimenez-Roqueplo,2 and Pierre Rustin1
1
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 676, Hôpital Robert Debré,
Paris; and 2Département de Génétique, Hôpital Européen Georges Pompidou, Assistance PubliqueHôpitaux de Paris, Université Paris V and INSERM Unité 772, Collège de France, Paris, France
mitochondria; fumarase; succinate dehydrogenase; cancer; encephalopathy
THE TRICARBOXYLIC ACID (TCA) cycle, also known as the Krebs
cycle, has long been considered so crucial for the basal metabolism of cell that no significant and primary defect in any of
its enzyme components could be compatible with life (59, 63).
On the basis of this assumption, anomalies in intermediate
metabolites were regarded as secondary phenomena, e.g., high
fumaric aciduria in patients. However, genetic studies finally
demonstrated that high fumarate excretion in the urine of
patients with progressive encephalopathy indeed resulted from
primary mutations in the fumarase hydratase (FH)-encoding
gene (7, 47, 65). It was further shown that, far from being
restricted to rare cases of encephalopathy, the total loss of FH
unexpectedly results in uterine fibroids, skin leiomyomata, and
papillary renal cell cancer (58). This raised a number of new
questions on the intricate and intriguing role of TCA cycle
enzymes, organic acid metabolism, and oxygen handling in
controlling cell proliferation (49). Integrating these new perspectives on the TCA cycle function motivates this review.
Tumorigenesis and intermediary metabolism have a long
common history. As early as 1926, Otto Warburg pioneered a
large field of researches devoted to the metabolism of tumor
cells (62). He thus reported a spectacular shift from a normal
aerobic metabolism to a highly glycolytic metabolism (despite
aerobic conditions) associated with the low respiration rate that
characterizes tumor cells. A few years later, in 1937, Hans
Krebs, one of his former students (and yet a mediocre one: Otto
Warburg judged that Hans Krebs’s knowledge in chemistry
was simply inadequate for a biochemist and advised him to
return to medicine. . .; Ref. 53), elucidated the cycle of reactions today known as the TCA cycle (33), which turned to be
the main source of the reducing molecules NADH and FADH2
Address for reprint requests and other correspondence: P. Rustin, INSERM
U676, Hôpital Robert Debré, Batiment Ecran, 48, Boulevard Sérurier, 75019
Paris, France (e-mail: [email protected]).
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sustaining mitochondrial respiratory chain activity and therefore the major source of energy in living organisms (Fig. 1).
Gathering these two major discoveries led to the belief that
tumorigenesis was linked to a change in the balance between
the TCA cycle and the glycolysis activity. But this oversimplified view was afterwards challenged by a number of observations, including the high requirement of tumor cells for an
active lipogenesis [see recent review by Costello and Franklin
(19)].
THE TCA CYCLE: STRUCTURE AND FUNCTION
Since its formalization by Hans Krebs, the TCA cycle has
proved to be a major turntable of the cell metabolism (33). The
conversion of reducing power provided by the carboxylic acids
into the respiratory chain-usable reduced coenzymes NADH
and FADH2 constitutes a main function of the TCA. However,
a number of cells, including mammalian cells, can survive the
nonutilization of these cofactors by the respirator chain [rho
zero cells devoid of respiratory chain due to the lack of
mitochondrial DNA (mtDNA)] (31). The TCA also ensures a
central role in an endless series of metabolic paths in particular,
thanks to transamination reactions (24). Several major anaplerotic pathways require the TCA cycle-catalyzed breakdown of
acetyl coenzyme A (acetyl-CoA) and the multistep interconversion of carbon skeletons delineated by Krebs (60). Finally,
TCA cycle should also be considered as a water-splitting
process generating oxygen for acetyl-CoA oxidation (64). Two
reactions of the TCA cycle consume one H2O molecule, each
furnishing oxygen for CO2 generation and oxidative reactions,
namely, the synthesis of citrate from acetyl-CoA and oxaloacetate (OOA) and the formation of malate from fumarate (Fig.
1B). Atmospheric oxygen is only used by the terminal oxidase
of the respiratory chain, the cytochrome oxidase, to ensure the
reoxidation of reduced coenzymes.
0363-6143/06 $8.00 Copyright © 2006 the American Physiological Society
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Brière, Jean-Jacques, Judith Favier, Anne-Paule Gimenez-Roqueplo, and
Pierre Rustin. Tricarboxylic acid cycle dysfunction as a cause of human diseases
and tumor formation. Am J Physiol Cell Physiol 291: C1114 –C1120, 2006. First
published June 7, 2006; doi:10.1152/ajpcell.00216.2006.—A renewed interest in
tricarboxylic acid cycle enzymopathies has resulted from the report that, in addition
to devastating encephalopathies, these can result in various types of tumors in
human. We first review the major features of the cycle that may underlie this
surprising variety of clinical features. After discussing the rare cases of encephalopathies associated with specific deficiencies of some of the tricarboxylic acid
cycle enzyme, we finally examine the mechanism possibly causing tumor/cancer
formation in the cases of mutations affecting fumarase or succinate dehydrogenase
genes.
Invited Review
TRICARBOXYLIC ACID CYCLE AND DISEASES
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The TCA cycle comprises a series of eight reactions resulting in the progressive oxidative decarboxylation of the acetylCoA, mostly produced by the activity of the pyruvate dehydrogenase (Fig. 1B). In addition to pyruvate arising from the
glycolysis, the TCA cycle can be fed by carbon compounds
derived from fatty acid degradation or from the several amino
acids (glutamate, alanine, etc.). This conventional view of the
TCA cycle has nevertheless been challenged to account for the
complexity and the variety of the physiological conditions
encountered in different tissues. Thus TCA cycle-related enzyme equipment of mitochondria varies between species, and,
in one given species, between organs. Thus mitochondria
endowed with matrix malic enzyme can use malate as a major
fuel molecule for TCA cycle running, with malate then used as
AJP-Cell Physiol • VOL
a source of both pyruvate and OAA, through the reactions
catalyzed by the NAD⫹-malic enzyme and the malate dehydrogenase, respectively (34, 41). On the other hand, a number
of experimental data would be best accounted for if the TCA
cycle comprised two independent segments, allowing different
fluxes, extending from ␣-ketoglutarate (␣-KG) to OAA and
from OAA to ␣-KG, respectively (Fig. 1B). Working in close
connection with the aspartate amino acid transferase (reversibly producing aspartate and ␣-KG from OAA and glutamate
or the glutamate-pyruvate transaminase), it would consume or
produce glutamate and aspartate, requiring only catalytic
amounts of OAA or ␣-KG.
The TCA cycle takes place in the semifluid matrix space of
the mitochondria, cluttered with folded membranes, proteins,
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Fig. 1. The tricarboxylic acid (TCA) cycle
and related enzymes. A: the TCA cycle takes
place in the mitochondrial matrix (A), where
its enzyme components are packed as a series
of metabolons directly feeding reduced
equivalent to the respirasome insert within
the mitochondrial membrane further used to
generate ATP by the ATPasome. B: the reactions catalyzed by the several TCA cycle
enzyme components, featuring the sites of
production of reduced equivalent (boxed
text) and including the short-circuit within
the cycle by the transamination reaction catalyzed by the aspartate amino transferase. 1,
pyruvate dehydrogenase; 2, citrate synthase;
3, aconitase; 4, isocitrate dehydrogenase; 5,
␣-ketoglutarate dehydrogenase; 6, succinylCoA synthase; 7, succinate dehydrogenase;
8, fumarase; 9, malate dehydrogenase; 10,
aspartate amino transferase. ANT, adenine
nucleotide translocator; im, inner membrane;
om, outer membrane; RC, respiratory chain.
Invited Review
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TRICARBOXYLIC ACID CYCLE AND DISEASES
TCA CYCLE ENZYMOPATHIES CAUSING
NEURODEGENERATIVE DISEASES
The autosomic recessive disease due to mutation in the
fumarase gene, previously known as fumaric aciduria, is a
severe and early encephalopathy with seizures and muscular
hypotonia leading to growth and developmental delay, with
excessive excretion of urinary fumarate (7, 47). Because of the
similarity of the clinical features associated with succinate
dehydrogenase (SDH) and FH gene mutations, it was later
suggested that decreased SDH activity due to the accumulation
of fumarate consecutive to a loss of fumarase activity was the
link between the two genetic diseases (48).
The very first case of inherited SDH deficiency was found in
two sisters with a neurodegenerative disorder presenting as a
leukodystrophy (8). CT scan and MRI demonstrated small
symmetrical foci of necrosis in the substentia nigra and in the
basal ganglia typical of Leigh syndrome as well as diffuse
cerebral white matter abnormalities. These patients were homozygous for an Arg554Trp mutation within the Fp subunit
(SDHA subunit) causing a significant decrease in SDH activity. Thereafter, mutations of SDHA have been reported in only
four families (6, 8, 27, 43). Three cases presented with autosomal recessive Leigh syndrome. In one case, a child died at 5
mo of age from a severe deterioration of neuromuscular,
cardiac, and hepatic symptoms after an intermittent infection.
Patients with an inherited deficiency of the ␣-KGDH present a
progressive, severe encephalopathy with axial hypotonia, psychotic behavior, and pyramidal symptoms (25). Children exhibit permanent lactic acidosis, with acute episodes during
emotional stress, and various infections associated with elevated lactate/pyruvate ratio and slightly decreased ketone body
ratio in the plasma.
An abnormal urinary excretion of organic acids was frequently noticed in those patients with TCA cycle enzyme
deficiency, with occasional peaks of ␣-KG observed whatever
the enzyme deficiency (␣-KGDH, SDH, or FH). This excretion
of ␣-KG suggested that in all these cases, the activity of the
␣-KHDH is decreased, potentially due to sequestration of CoA
between various CoA esters in case of SDH and fumarase
deficiency.
Succinyl-CoA synthetase (ADP forming) mutations result in
autosomal recessive encephalopathy and Leigh syndrome (21).
Secondary depletion of mtDNA was also noticed in these
patients. The physical interactions between the succinyl-CoA
synthetase and the nucleoside diphosphate kinase, which might
be involved in the phosphorylation of the mitochondrial deoxyribonucleotide diphosphates, suggest a role for the former
enzyme in the synthesis of the deoxynucleotide triphosphates
of the mitochondria. This may account for mtDNA depletion
and the consecutive loss of the activity of respiratory chain
complexes containing subunits encoded by the mitochondrial
genome. Because of the occurrence of a second succinyl-CoA
synthetase (GDP-forming succinyl-Coa synthetase), the activity of the TCA cycle should be less affected than in the case of
SDH, FH, or ␣-KGDH mutations. As a result, a defect in the
respiratory chain rather than TCA cycle dysfunction may be at
the origin of the disease.
Table 1. TCA enzymopathies and diseases
Enzyme
␣-Ketoglutarate dehydrogenase
Succinate dehydrogenase
Gene
Fumarase
OGDH
SDHA
SDHB
SDHC
SDHD
FH
Succinyl-CoA synthetase (ADP forming)
SUCLA2
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Disease
Severe encephalopathy, hypotonia, psychotic behavior, pyramidal symptoms
Leigh syndrome
Paraganglioma and pheochromocytoma
Paraganglioma
Paraganglioma and pheochromocytoma
Early encephalopathy, seizures, and muscular hypotonia
Leiomyomatosis and papilliary renal cell cancer
Encephalomyopathy and mtDNA depletion
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and RNA and DNA molecules, spatially and kinetically compartmented. Increasing efficient operation of the cycle, metabolically related enzymes are associated into metabolons ensuring channeling of substrates through selected sets of enzymes (Fig. 1A) (55). Accordingly, the TCA cycle enzymes are
consistently found in balanced proportions depending on different tissues (44), suggesting a concerted expression of the
genes coding for TCA cycle enzymes to fit tissue-specific
metabolic demand. The semifluid state of the matrix also
results in a kinetic compartmentation of soluble oxidation
cofactors, such as NAD⫹ (50), together with the several dehydrogenases.
Citrate synthase, isocitrate, and ␣-KG dehydrogenase (␣KGDH) activities are the major regulatory steps controlling the
flux through the entire cycle (59). Regulation also involves the
substrate supply, the pyridine nucleotide redox poise and
concentration (NADH/NAD⫹), the coenzyme A availability,
the matrix phosphorylation potential (Pi ⫹ ADP/ATP ratio),
and the Ca2⫹ concentration that regulate several steps of the
TCA cycle.
Finally, a wealth of evidence has accumulated establishing
that thyroid hormones and glucocorticoids influence the activity of the TCA cycle. Thyroid hormone-induced increase of
mitochondrial Ca2⫹ and substrate supply would stimulate the
overall TCA cycle activity. In addition, the control of mitochondrial biogenesis by thyroid hormones and glucocorticoids,
exerted at both transcriptional and translational levels, results
in the broader term effect of hormones on TCA cycle activity
(54). The TCA cycle enzymes are all nuclearly encoded. The
15 nuclear genes coding for the protein moieties constitutive of
the 9 TCA cycle mitochondrial enzymes have now been
localized in humans, and most of the corresponding cDNAs
have been cloned and sequenced (46). Four of the enzymes
possess both a mitochondrial and a cytosolic form. As far as
the fumarase is concerned, two isoenzymes have been identified and shown to be encoded by a single gene. Their distribution varies among tissues, the cytosolic form being absent in
the brain (1). The mechanism of their distribution raises intriguing questions that have been a matter of debate (29, 57).
Invited Review
TRICARBOXYLIC ACID CYCLE AND DISEASES
SDH B-, C-, AND D-SUBUNIT-ENCODING GENES ACT AS
TUMOR SUPPRESSOR IN NEUROENDOCRINE TISSUES
Three of the four subunits of complex II, namely, SDHB,
SDHC, and SDHD, have been involved in the tumorigenesis
resulting in paragangliomas and pheochromocytomas (4). Most
probably, the presence of two SDHA forms in neuroendocrine
tissues accounts for the absence of paraganglioma associated
with SDHA mutations (11). All SDH-hereditary paragangli-
oma are transmitted according to an autosomic dominant mode
of inheritance. However, in the case of SDHD-related syndrome, a maternal genomic imprinting is associated with the
dominant transmission, and the disease is only transmitted by
the paternal branch (4).Theses tumors are mostly benign,
highly vascularized, and slow growing. They result from a
germline heterozygous mutation associated with a loss of the
wild type allele in the tumoral tissue, inducing a specific loss of
SDH enzymatic activity (23). Paragangliomas caused by SDH
deficiency generally occur from parasympathetic ganglia in the
head and the neck (mostly in the carotid body) and from
sympathetic ganglia in the thorax, the abdomen, and the pelvis.
Pheochromocytomas are derived from the chromaffin cells of
the adrenal medulla. The only curative therapy is the early
surgical resection of the tumors (22). Noticeably, paragangliomas of the carotid body can be caused by chronic hypoxia as
well, as observed in patients living in high altitude or suffering
from chronic obstructive pulmonary disease (30). Mutations in
SDHB and SDHD genes have been found in patients harboring
both paragangliomas and pheochromocytomas (3, 5), whereas
SDHC mutations have only been found in patients with head
and neck paragangliomas to date (51).
FUMARASE MUTATION PREDISPOSES TO CUTANEOUS AND
UTERINE LEIOMYOMAS AND PAPILLIARY RENAL
CELL CANCER
More than 40 mutations in the fumarase gene have been
reported to cause uterine and/or cutaneous leiomyomas (58). In
a subset of these cases, leiomyomas are associated with pap-
Fig. 2. The TCA cycle and human diseases: a schematized
view of our present knowledge on the consequences of
impairing TCA cycle enzyme activity (specific blockade
indicated by dotted lines) on the clinical features observed
in humans. AAT, aspartate amino transferase; ACO, aconitase; A-CoA, acetyl-CoA; asp, aspartate; cit, citrate; CS,
citrate synthase; FUM, fumarase; fum, fumarate, glu, glutamate; IDH, isocitrate dehydrogenase; iso, isocitrate;
␣-KG, ␣-ketoglutarate; KGDH, ␣-ketoglutarate dehydrogenase; mal, malate; MDH, malate dehydrogenase; oaa,
oxaloacetate; PDH, pyruvate dehydrogenase; Pyr, pyruvate; S-CoA, succinyl-CoA; SCA, succinyl-CoA synthase;
SDH, succinate dehydrogenase; succ, succinate.
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To this list of TCA cycle-specific enzymopathies (Table 1
and Fig. 2), one should add Friedreich ataxia, which associates
a severe aconitase and SDH defect to a respiratory chain
disorder (complex I and III deficiencies) (48). All the defective
enzymes in Friedreich ataxia share iron-sulfur clusters as
essential components in their catalytic activity. Accordingly,
the frataxin protein lacking its function in Friedreich ataxia has
been shown to be involved in the biosynthesis of iron-sulfur
cluster (56) due to improper handling of iron, which renders
cells hypersensitive to oxidative insults (14). As a matter of
fact, there is compelling evidence that iron-sulfur clusters are
exquisitely sensitive to superoxides and thus are often found to
be more or less severely affected in cases of oxidative insults
(40, 42). Accordingly, SDH activity is often found to be
decreased in case of mitochondrial ATPase defects known to
result in the release of large amounts of superoxides (12).
Finally, a consistent observation that can be made in patients
suffering any of these TCA cycle defects deals with the tissue
specificity of these diseases, which has not yet received a
rational explanation (10).
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Invited Review
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TRICARBOXYLIC ACID CYCLE AND DISEASES
illiary renal cell cancer, resulting in the so-called hereditary
leiomyomatosis and renal cell cancer (HLRCC) syndrome.
Recent studies found that a vast majority of patients presenting
skin leiomyomas (up to 85%) had deleterious mutations in the
fumarase gene (2).
SDH AND FH TUMORS, A COMMON PATHWAY?
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The prostate gland cells are characterized by their extraordinary high levels of citrate (40,000 –150,000 nmol/g) and
intracellular zinc (⬃1,000 ␮g/g) (16, 26). Under physiological
conditions, the activity of the mitochondrial aconitase is turned
down by the presence of zinc, contributing to citrate accumulation (18). The accumulated citrate is then secreted into the
semen. High accumulation of zinc also inhibits the respiratory
chain, reducing energy production usually produced by the
respiratory chain and the TCA cycle. In prostate cancer cells,
the level of secreted citrate is lowered due to a switch in the
metabolism of the tumoral cell. Citrate is then actively oxidized due to a decreased zinc content and an increased aconitase activity (17). TCA cycle is then functional, as is the
respiratory chain as well. So, in contrast to the previously
described conditions where accumulated organic acids results
in tumor formation, a normal TCA functioning paradoxically
results in the activation of a tumoral process.
A PROVISIONAL CONCLUSION
So far only a subset of the components of the TCA cycle has
been found to be defective in humans. Yet, the clinical spectrum encompasses a large variety of diseases, ranging from
devastating encephalopathies to tumor formation and cancers.
The predictable consequences of a TCA cycle blockade are
multiple, but it already appears that the impairment of each of
the TCA cycle steps is susceptible to result in highly specific
features. Indeed, if severe defects of several of the enzymes
result in overlapping clinical features already observed in cases
of pyruvate dehydrogenase and respiratory chain deficiency,
suggestive of a common mechanism presumably linked to
energetic failure, some of the defects result in much more
specific features such as tumor formation and/or cancer. In
these latter cases, the mechanism that triggers cell proliferation
appears to be mainly associated with imbalance in the organic
acids controlling the prolyl hydroxylase enzyme. Specific organic acids ultimately cause HIF-1␣ nuclear translocation,
allowing for angiogenesis and cell proliferation.
Initially disregarded as a primary cause of human diseases
because of a predicted lethality, several inherited TCA cycle
deficiencies were proved in the mid-1990s to result in encephalopathies in humans. Even more unexpected was the link
recently established between organic acid accumulation and
abnormal cell proliferation, resulting in tumor and/or cancer
formation. Our poor understanding of the highly variable
Table 2. TCA cycle proteins and mtDNA
stability in the yeast
Enzymes
Gene
mtDNA Stability
Aconitase
Isocitrate dehydrogenase
␣-Ketoglutarate dehydrogenase
Aco1
Idh1
Kgd1
Kgd2
Lpd1
Lsc1
Pda1
Pdb1
mtDNA total loss (rho 0)
Moderate instability
Moderate instability
Moderate instability
Moderate instability
Stable
Moderate instability
Moderate instability
Succinyl-Coa synthetase
Pyruvate dehydrogenase
TCA, tricarboxylic acid; mtDNA, mitochondrial DNA. Data are from Ref.
15.
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Hypoxia-inducible factors (HIFs) are major elements of the
cellular response to hypoxia. These transcription factors activate glycolysis, angiogenesis, and numerous targets when the
cell is short of oxygen (36). The involvement of HIFs has been
observed in numerous types of tumors, playing an active role in
the progression of the neoplasia (38). HIFs are composed of
two subunits, an ␣-subunit, which is regulated by oxygen, and
a ␤-subunit (HIF-1␤, also called the aryl hydrocarbon receptor
nuclear translocator, or ARNT), which is constitutively and
ubiquitously expressed. Three ␣-subunits have been identified
so far (HIF-1␣, HIF-2␣ and HIF-3␣), each encoded by a
different gene (61). Under normoxic conditions, HIF-␣ are
continuously ubiquitinated and subsequently degraded by the
proteasome (9). The process of ubiquitination is started by their
recognition by the von Hippel-Lindau (VHL) protein, which
requires the hydroxylation of two proline residues on HIF-␣
(39). The very first step of HIF-␣ degradation under normoxic
conditions is thus dependent of this hydroxylation, which is
catalyzed by HIF prolyl hydroxylases (PHDs). PHDs belong to
the superfamily of Fe(II)-dependant oxygenases and require
reduced iron as a cofactor, ␣-KG and oxygen as cosubstrates,
with carbon dioxide and succinate being the products of the
reaction (13). Under hypoxic conditions, the absence of oxygen
prohibits PHD activity, and HIF-␣ are thus stabilized, allowing
for their nuclear translocation and the subsequent activation of
their target genes.
Four years after the seminal observation in 2001 of the
putative implication of HIFs in a paraganglioma due to a
mutation in the SDHD gene (23), it was recently shown that the
high concentration of succinate accumulated in tumors (45), or
in SDH-deficient cells (11) directly linked to the loss of SDH
activity, was sufficient to affect PHD activity in vitro (28, 52).
Similar to hypoxia, succinate accumulation could therefore
induce the inhibition of the PHD, allowing for the nuclear
translocation of HIF-1␣. Recently, a very similar mechanism
was described for FH deficiency in a renal cell cancer (28, 45).
In this latter case, fumarate, accumulated due to fumarase
inactivation, was found to act as a competitive inhibitor of the
PHD, thus inducing the abnormal stabilization of HIF-1␣.
Noticeably, other structurally related organic acids can also
inhibit the PHD (20). Therefore, a TCA cycle blockade may
result in the induction of angiogenesis and in the tuning up of
the glycolysis during tumorigenesis, being at the origin of the
Warburg effect. These observations support the view that
hypoxia-inducible factors play a central role in tumorigenesis
of the neuroendocrine system. Accordingly, in the VHL syndrome, characterized by the presence of hemangioblastomas,
renal cell carcinomas, and pheochromocytomas, abnormal activation of HIF-2␣ caused by mutations in the VHL gene has
been suggested to be directly responsible for tumorigenesis
(32, 37). However, this proposal has been challenged by the
observation that in pheochromocytomas, HIF activity is not per
se the tumorigenic cause of VHL mutation (35).
ACONITASE, CITRATE, ZINC AND PROSTATE CANCER
Invited Review
TRICARBOXYLIC ACID CYCLE AND DISEASES
phenotypes associated with an impairment of the TCA cycle
may stand from our substantial ignorance of a number of issues
related to TCA cycle, especially dealing with tissue-to-tissue
differences in enzyme activity and the role of organic acids.
Finally, the potential multifunctional roles of these enzymes,
already partially recognized in yeast (15) (Table 2), suggests
that new surprises are to be found around the corner in the
years to come.
GRANTS
We thank the Association Française contre les myopathies, the GIS-Institut
des Maladies Rares for the PGL.NET Network, and the Integrated Project
Eumitocombat for their support.
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