Mitochrondrial Gateways To Cancer

Review
Mitochondrial gateways to cancer

Lorenzo Galluzzi
a,b,c,1
, Eugenia Morselli
a,b,c,1
, Oliver Kepp
a,b,c,1
, Ilio Vitale
a,b,c
, Alice Rigoni
a,b,c
,
Erika Vacchelli
b,c,d
, Mickael Michaud
a,b,c
, Hans Zischka
e
, Maria Castedo
a,b,c
, Guido Kroemer
a,b,c,
*
a
INSERM, U848, Institut Gustave Roussy, PR1, 39, rue Camille Desmoulins, F-94805 Villejuif, France
b
Institut Gustave Roussy, F-94805 Villejuif, France
c
Universit Paris-Sud XI, F-94805 Villejuif, France
d
INSERM, U805, F-94805 Villejuif, France
e
Institute of Toxicology, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Oberschleissheim, Germany
a r t i c l e i n f o
Article history:
Received 26 May 2009
Received in revised form 12 August 2009
Accepted 13 August 2009
Keywords:
Bcl-2
Caspases
Mitochondrial transmembrane potential
Oncoproteins
p53
Tumor suppressors
a b s t r a c t
Mitochondria are required for cellular survival, yet can also orchestrate cell death. The
peculiar biochemical properties of these organelles, which are intimately linked to their
compartmentalized ultrastructure, provide an optimal microenvironment for multiple bio-
synthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial
respiration, which also represents the most relevant source of intracellular reactive oxygen
species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol,
cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numer-
ous pro-survival and pro-death signals, thereby exerting a decisive control over several
biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis.
Therefore, it is not surprising that cancer cells often manifest the deregulation of one or
several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replica-
tion, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, dis-
abled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as
other common features of tumors (i.e., avoidance of the immune response, enhanced ana-
bolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated
mitochondria. In this review, we discuss several mechanisms by which mitochondria can
contribute to malignant transformation and tumor progression.
2009 Elsevier Ltd. All rights reserved.
0098-2997/$ - see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mam.2009.08.002
Abbreviations: ACL, ATP citrate lyase; AIF, apoptosis inducing factor; AML, acute myeloid leukemia; ANT, adenine nucleotide translocase; BH, Bcl-2
homology domain; CRT, calreticulin; CypD, cyclophilin D; Cyt c, cytochrome c; Dw
m
, mitochondrial transmembrane potential; DCA, dichloroacetate; ECM,
extracellular matrix; EMT, epithelialmesenchymal transition; EndoG, endonuclease G; ER, endoplasmic reticulum; FASN, fatty acid synthase; FH, fumarate
hydratase; HIF-1, hypoxia-inducible factor 1; HK, hexokinase; HSP, heat-shock protein; IjBa, inhibitor of jB a subunit; IjKb, IjB kinase b subunit; IM,
mitochondrial inner membrane; IMS, mitochondrial intermembrane space; IP
3
R, inositol 1,4,5-trisphosphate receptor; MAPK, mitogen-activated protein
kinase; MEFs, mouse embryonic broblasts; MMP, mitochondrial membrane permeabilization; MnSOD, manganese superoxide dismutase; MOMP,
mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; mtCK, mitochondrial creatine kinase; OM, mitochondrial
outer membrane; PBR, peripheral benzodiazepine receptor; PDGF, platelet-derived growth factor; PDH, pyruvate dehydrogenase; PDK1, PDH kinase 1; PET,
positron emission tomography; PFK2, 6-phosphofructo-2-kinase; PI3K, phosphatidylinositol-3 kinase; PINK1, PTEN induced putative kinase 1; PKM2,
pyruvate kinase M2 isoform; PTPC, permeability transition pore complex; RNAi, RNA interference; ROS, reactive oxygen species; SDH, succinate
dehydrogenase; siRNA, small interfering RNA; Stat, signal transducer and activator of transcription; TCA, tricarboxylic acid; TGF b, transforming growth
factor b; TSPO, translocator protein of 18 kDa; VDAC, voltage-dependent anion channel.
* Corresponding author. Address: INSERM, U848, Institut Gustave Roussy, PR1, 39, rue Camille Desmoulins, F-94805 Villejuif, France. Tel.: +33 1 4211
6046; fax: +33 1 4211 6047.
E-mail address: kroemer@orange.fr (G. Kroemer).
1
These authors equally contributed to the article.
Molecular Aspects of Medicine 31 (2010) 120
Contents lists available at ScienceDirect
Molecular Aspects of Medicine
j our nal homepage: www. el sevi er . com/ l ocat e/ mam
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1. Mitochondria in cell life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2. Mitochondria in cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. General implication of mitochondria in tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Limitless proliferative potential and mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Immortalization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.2. Self-sufficient growth signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.3. Insensitivity to antiproliferative signals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.4. Disabled cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4. Angiogenesis, invasiveness, metastatic potential and mitochondria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. Avoidance of the immune response and mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
6. Metabolic reprogramming and mitochondria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1. Introduction
Mitochondria are indispensable for the survival of higher eukaryotic cells, including cancer cells. At the same time, these
organelles hide the weapons of cellular suicide, meaning that they control cell death. The scope of this introduction is to
briey review the quintessential vital and lethal functions of mitochondria.
1.1. Mitochondria in cell life
The essential participation of mitochondria in cellular functions has been highlighted more than one century ago. Orig-
inally described as bioplasts (Altmann, 1890), these organelles were soon renamed due to their threadlike appearance dur-
ing spermatogenesis (mitos = thread, chondros = granule) (Benda, 1898). The rst attempt to isolate mitochondria was
launched in the thirties (Ernster and Schatz, 1981), approximately at the same time as Warburg described the fundamentals
of cancer cell metabolism (Warburg et al., 1930). Around and after Wold War II, the basic biochemical reactions underlying
cellular respiration were revealed, culminating with Mitchells chemiosmosis hypothesis on the conservation of energy in
the form of a proton gradient across the mitochondrial inner membrane (IM) (Mitchell, 1961; Ernster and Schatz, 1981).
The most important biochemical cascade conned to mitochondria is oxidative phosphorylation, a coordinated series of
redox reactions catalyzed by ve multi-subunit enzymatic activities embedded in the IM (i.e., respiratory complexes IIV and
the F
1
F
O
-ATP synthase) and two soluble factors (i.e., cytochrome c, Cyt c; coenzyme Q10), that function as electron shuttles
within the mitochondrial intermembrane space (IMS). Oxidative phosphorylation results in the generation of an electro-
chemical gradient across the IM that is dissipated in a controlled fashion by the F
1
F
O
-ATP synthase to generate the bulk
of intracellular ATP stores (Mitchell, 1961; Reichert and Neupert, 2004). In a healthy eukaryotic cell, around 2.000 mitochon-
dria produce more than 90% of intracellular ATP (Voet and Voet, 1995; Pedersen, 2007). Additional metabolic pathways that
are located within mitochondria include the Krebs cycle, heme biosynthesis, b-oxidation of fatty acids, steroidogenesis, the
metabolism of certain amino acids as well as the formation of Fe/S clusters (Reichert and Neupert, 2004). Moreover, mito-
chondria host the initial steps of ammonium detoxication (by the urea cycle, also known as KrebsHenseleit cycle) as well
as reactions belonging to gluconeogenesis and ketogenesis (Michal, 1999) (Fig. 1).
Beside their role as ubiquitous power plants, mitochondria serve in a highly specialized fashion the needs of their host
tissue cells, which results in signicant tissue-dependent variations of their activity (including Ca
2+
homeostasis) (Campa-
nella et al., 2004; Rizzuto and Pozzan, 2006) and molecular composition (Mootha et al., 2003). A comparative proteome anal-
ysis of mitochondria obtained from different murine organs (i.e., liver, brain, heart and kidney) revealed that only half of bona
de mitochondrial proteins are omnipresent, while the other half have 50% probability to occur in a given tissue (Mootha
et al., 2003). This implies that current estimates of the total number of mitochondrial proteins might have to be revised. Cur-
rently, the MITOP2 database for human mitochondria lists a reference set that includes around 900 proteins with a veried
mitochondrial localization. Importantly, depletion and/or malfunction of almost 200 of these proteins have been linked to
human disease (http://www.mitop.de:8080/mitop2/). We surmise that this is just the tip of the iceberg and that system biol-
ogy approaches will unravel the existence of additional mitochondrial components playing important roles in health and
disease.
1.2. Mitochondria in cell death
Mitochondrial membrane permeabilization (MMP) is widely considered as the point of no return in the cascade of events
leading to cell death via intrinsic apoptosis (Kroemer et al., 2007), as well as through non-apoptotic cell death subroutines
2 L. Galluzzi et al. / Molecular Aspects of Medicine 31 (2010) 120
(Galluzzi et al., 2007, 2009; Kroemer et al., 2009). Under conditions of stress, lethal and vital signals are opposing each other
at the level of mitochondrial membranes. If pro-death stimuli predominate, MMP takes place and leads to a series of cata-
strophic consequences that eventually seal the cells fate. These include (but are not limited to) the dissipation of the mito-
chondrial transmembrane potential (Dw
m
), which immediately results in the arrest of mitochondrial ATP synthesis and of
several other biosynthetic pathways, as well as the mitochondrio-cytosolic translocation of numerous proteins that are nor-
mally conned within the IMS, where they exert vital functions (Kroemer et al., 2007; Galluzzi et al., 2008a). These factors
can be subdivided into three broad categories: direct caspase activators (e.g., Cyt c), indirect caspase activators (e.g., Smac/
Diablo; Omi/HtrA2) and caspase-independent cell death effectors (e.g., apoptosis inducing factor, AIF; endonuclease G,
Fig. 1. Mitochondria in cell life. Through oxidative phosphorylation, mitochondria produce the bulk of intracellular ATP, and hence are considered the cells
power plants. In addition, mitochondria regulate Ca
2+
homeostasis and host (at least some steps of) several other metabolic circuitries including (but not
limited to) the Krebs cycle, the urea cycle, gluconeogenesis, ketogenesis, heme biosynthesis, fatty acid b-oxidation, steroidogenesis, the metabolism of
certain amino acids and the formation of Fe/S clusters. ER, endoplasmic reticulum; PM, plasma membrane.
Fig. 2. Mitochondria in cell death. Upon activation by BH3-only proteins, pro-apoptotic multidomain members of the Bcl-2 family (e.g., Bax, Bak) fully insert
into the mitochondrial outer membrane, oligomerize and form protein-permeable channels, thereby inducing mitochondrial outer membrane
permeabilization (MOMP, upper left panel). In other circumstances (e.g., under oxidative stress), mitochondrial permeability transition (MPT, lower left
panel) is initiated at the inner mitochondrial membrane, due to the opening of the supramolecular protein complex known as permeability transition pore
complex (PTPC). Both MOMP and MPT eventually lead to the cytosolic spillage of proteins that normally reside within the mitochondrial intermembrane
space. This ignites caspase-dependent and -independent biochemical cascades that execute cell death (right panel). Please refer to the main text for further
details. AIF, apoptosis inducing factor; Cyt c, cytochrome c; Dw
m
, mitochondrial transmembrane potential; EndoG, endonuclease G.
L. Galluzzi et al. / Molecular Aspects of Medicine 31 (2010) 120 3
EndoG). Once in the cytosol, IMS proteins activate caspase-dependent and -independent mechanisms that altogether medi-
ate the execution of cell death (Kroemer et al., 2007) (Fig. 2).
MMP can result from two distinct, yet partially overlapping mechanisms (Kroemer et al., 2007). Upon activation, multi-
domain pro-apoptotic members of the Bcl-2 protein family may form protein-permeable pores in the mitochondrial outer
membrane (OM), a process known as mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release
of IMS proteins into the cytosol, among which soluble components of the respiratory chain, whose depletion (eventually)
leads to respiratory chain uncoupling and Dw
m
loss (Fig. 2). Anti-apoptotic proteins from the Bcl-2 family (e.g., Bcl-2, Bcl-
X
L
) also (but not only) act by sequestering their pro-apoptotic counterparts into inactive complexes, which can be disrupted
by pro-apoptotic BH3-only proteins (Willis and Adams, 2005).
Alternatively, MMP can be ignited at the mitochondrial inner membrane (IM), due to the opening of a supramolecular
entity that is assembled at the junctions between the OM and the IM and that is known as the permeability transition pore
complex (PTPC). The PTPC normally ensures the exchange of metabolites between the cytosol and the mitochondrial matrix,
but can also mediate the so-called mitochondrial permeability transition (MPT). This process consists in an abrupt loss of
the impermeability of the IM to solutes, immediately followed by Dw
m
dissipation and osmotic swelling of the mitochon-
drial matrix, which eventually leads to OM breakdown and spillage of IMS proteins into the cytosol (Fig. 2). The PTPC has
been described as a very dynamic structure, and its precise molecular composition is still debated. However, some consensus
exists on the components that would constitute its backbone, including the voltage-dependent anion channel (VDAC) in the
OM, the adenine nucleotide translocase (ANT) in the IM, and cyclophilin D (CypD) in the mitochondrial matrix. Importantly,
both pro- and anti-apoptotic members of the Bcl-2 protein family have been shown to interact with the PTPC (Marzo et al.,
1998a,b), suggesting that MOMP- and MPT-driven MMP are not completely independent from each other.
2. General implication of mitochondria in tumorigenesis
As mitochondria play a critical role in numerous bioenergetic, anabolic and cell death-inducing biochemical pathways, it
is not surprising that mitochondrial dysfunction contributes to the development of a plethora of human diseases, which
range from highly tissue-specic conditions to generalized whole-body disorders including cancer (Taylor and Turnbull,
2005). Several common features of established tumor cells can directly or indirectly result from mitochondrial deregulation
(see below). Moreover, mitochondria may be implicated in early tumorigenesis, as cancer progenitor cells appear, replicate
and progressively acquire a malignant phenotype.
A number of conditions can lead to the intramitochondrial overgeneration of reactive oxygen species (ROS), which favor
oxidative damage-dependent mutagenesis and hence promote tumorigenesis (Zhou et al., 2007). Mutations of the nuclear or
mitochondrial DNA (mtDNA) may affect components of the respiratory chain (e.g., cytochrome b) and favor uncoupling,
which results in increased electron leakage and ROS overproduction (Dasgupta et al., 2008). Such mutations are found in
a wide variety of cancer types (Modica-Napolitano and Singh, 2004). Old or damaged mitochondria produce high levels of
ROS, but are normally degraded through mitophagy, a specialized branch of macroautophagy that selectively targets these
organelles to lysosome-mediated disposal (Tolkovsky, 2009). As the molecular machineries for mitophagy and macroauto-
phagy partially (but not completely) overlap (for a review see (Klionsky et al., 2007) and (Xie and Klionsky, 2007)), a reduced
mitophagic ow may derive either from defects in general autophagic modulators (e.g., Beclin 1) (Yue et al., 2003) or from
mitophagy-specic decits (Schweers et al., 2007). Irrespective of the underlying mechanisms, insufcient clearance of old/
damaged mitochondria may favor malignant transformation (Morselli et al., 2009).
It has been postulated that a mitochondrial damage checkpoint (mitocheckpoint) would be turned on by mitochondrial
derangement, thereby preventing cell cycle progression until the restoration of mitochondrial functions (Singh, 2006). In
conditions of excessive mitochondrial injury, the mitocheckpoint would activate senescence, thereby acting as a bone de
tumor suppressor mechanism (Singh, 2006). Although the precise molecular mechanisms remain unidentied, it has been
suggested that mitocheckpoint-triggered senescence would mimic the pathway of senescence triggered by telomere attri-
tion (Campisi, 2005; Singh et al., 2005). This implies that mitochondrial dysfunction would favor tumorigenesis only when
the senescence program has been inactivated.
In a milestone article published in 2000, Hanahan and Weinberg enumerated six hallmarks that characterize most human
cancers: limitless proliferative potential, self-sufcient growth signaling, insensitivity to antiproliferative signals, disabled
apoptosis, sustained angiogenesis and invasiveness/metastatic potential (Hanahan and Weinberg, 2000). More recently,
other common features of tumor cells have been proposed, including enhanced anabolism (Kroemer and Pouyssegur,
2008), avoidance of the immunosurveillance (Zitvogel et al., 2008), and suppressed autophagy (Morselli et al., 2009). As dis-
cusses in the following sections, several among these characteristics may be directly/indirectly linked to mitochondria.
3. Limitless proliferative potential and mitochondria
Tumor cells of distinct origin share the ability to proliferate in an uncontrollable fashion, both in vitro and in vivo. This
proliferative potential results from multiple molecular defects. First, in contrast to normal cells, tumor cells are immortal-
ized, meaning that they can replicate in a limitless fashion without undergoing senescence. Frequently, this involves the
acquisition of constitutive telomerase expression, which prevents the erosion of telomeres that normally occurs with aging
(Dong et al., 2005). Second, cancer cell proliferation often does not depend on extrinsic signals. Gain-of-function mutations
that affect growth factor-activated signaling cascades and/or the non-physiological autocrine/paracrine production of
growth factors constitute two of the possible mechanisms by which tumor cells emancipate from the proliferative control
normally exerted by the local microenvironment (Gschwind et al., 2004). Finally, as compared to their normal counterparts,
tumor cells are resistant to antiproliferative signals, as well as to multiple stress conditions that usually trigger cell death
(Igney and Krammer, 2002; Gatenby and Gillies, 2004). Loss-of-function mutations in genes that encode cell cycle arresting
(e.g., p21
Cip1
) and pro-apoptotic (e.g., Bax, caspases) proteins, as well as the genetic/epigenetic upregulation of cell cycle pro-
moting (e.g., cyclin D1) and anti-apoptotic (e.g., Bcl-2) modulators are found in a relevant fraction of human cancers (Baur
et al., 1999; Nakamura et al., 2001; Sakuragi et al., 2002; Rassidakis et al., 2003; Soung et al., 2005; Tashiro et al., 2007).
3.1. Immortalization
hTERT, which is overexpressed in most tumor cells, is the catalytic subunit of telomerase and is required for the mainte-
nance of telomere length (Masutomi et al., 2003). Therefore, hTERT is commonly believed to act in the nucleus. However, due
to a bona de mitochondrial targeting sequence, hTERT is also found in mitochondria, where it maintains its catalytic activity
(Santos et al., 2004). Early studies based on the overexpression of catalytically-procient hTERT variants selectively targeted
to mitochondria or the nucleus suggested that mitochondrial hTERT would enhance oxidative stress-mediated mtDNA dam-
age and cell death, whereas nuclear hTERT would indirectly exert cytoprotective effects (Santos et al., 2006). These observa-
tions are in contrast with recent results demonstrating that endogenous hTERT translocates to mitochondria in conditions of
oxidative stress, thereby binding mtDNA, increasing respiratory chain activity and preserving Dw
m
(Ahmed et al., 2008;
Haendeler et al., 2009). Moreover, the unselective depletion of hTERT via RNA interference (RNAi) has been shown to sen-
sitize cervical and colon carcinoma cells to multiple cell death triggers (including oxidative stress) (Massard et al., 2006; Xi
et al., 2006). As this chemosensitizing effect was observed within 48 h after transfection of hTERT-specic small interfering
RNAs (siRNAs), it cannot be attributed to the attrition of telomeres (Massard et al., 2006). Finally, there are many examples in
which the overexpression of wild-type hTERT resulted in increased resistance to mitochondrial apoptosis (Zhang et al.,
2003b; Xi et al., 2006; Ahmed et al., 2008). Altogether, these observations suggest that hTERT protects mitochondria against
MMP, thereby inhibiting the intrinsic pathway of apoptosis. The precise mechanisms accounting for the MMP-inhibitory
function of hTERT have not yet been elucidated.
Expression-proling of primary breast tumor cultures pre- and post-hTERT transduction, and spontaneously immortal-
ized breast cancer cell lines has been employed to identify an ensemble of molecular features characteristic of tumor cell
immortalization (Dairkee et al., 2007). Such an immortalization signature was characterized by the overexpression of oxi-
doreductase genes that affected multiple mitochondrial parameters (including Dw
m
and ROS production), and could be re-
versed by hTERT silencing. In clinical breast cancer samples, the expression of components of the immortalization signature
was inversely correlated with patient survival. These results suggest that hTERT activates transcriptional programs that favor
cancer-associated mitochondrial alterations (Dairkee et al., 2007).
Mortalin (which is also known as mtHsp70, Hsp75, GRP75, and PBP74) is a constitutively expressed protein from the
heat-shock protein (HSP) family that was rst remarked for its differential localization in mortal vs. immortal cells (Wadhwa
et al., 1993). Thus, while mortal mouse embryonic broblasts (MEFs) contained mortalin in a cytosolic localization, their
immortalized counterparts presented mortalin in perinuclear clusters (Wadhwa et al., 1993). Mortalin is mainly found in
mitochondria but also in extra-mitochondrial compartments including the endoplasmic reticulum (ER) (Ran et al., 2000).
Depending on its subcellular distribution and on its binding partners, numerous functions have been ascribed to mortalin.
For instance, cytoplasmic mortalin is able to sequester the tumor suppressor protein p53, thereby inhibiting both its nuclear
(cell cycle arresting and/or pro-apoptotic) and extranuclear (pro-apoptotic) functions (Wadhwa et al., 2002). Moreover,
mortalin has been shown to indirectly affect the Ras-Raf signaling pathway (Wadhwa et al., 2003), which exerts a major con-
trol on cell proliferation and is often deregulated in human tumors (Schubbert et al., 2007), and to be phosphorylated by the
PTEN induced putative kinase 1 (PINK1), thereby mediating cytoprotective effects (Pridgeon et al., 2007). Finally, mortalin
reportedly antagonizes oxidative stress-induced cell death in a number of distinct experimental settings (Hua et al.,
2007; Voloboueva et al., 2008). In line with these observations, mortalin overexpression has been shown to signicantly en-
hance the tumorigenic potential of immortalized human embryonic broblasts, in vivo (Wadhwa et al., 2006), and has also
been identied as an independent negative prognostic variable in colorectal cancer patients (Dundas et al., 2005). In spite of
the multifaceted implication of mortalin in tumorigenesis and tumor progression, it remains unclear whether this mitochon-
drial HSP also exerts bona de immortalizing effects.
3.2. Self-sufcient growth signaling
GRIM-19 is a mitochondrial protein originally identied by virtue of its interaction with viral factors that modulate inter-
feron b- and retinoic acid-induced cell death (Seo et al., 2002). Subsequent yeast two-hybrid screenings suggested that
GRIM-19 can interact with signal transducer and activator of transcription 3 (Stat3), a latent cytoplasmic transcription factor
that is activated by several cytokines and growth signals (Lufei et al., 2003). Upon interaction with GRIM-19, Stat3 clustered
in perinuclear aggregates but could not translocate to the nucleus, thereby losing its function as a transcription factor (Lufei
et al., 2003). GRIM-19 has been shown to inhibit Stat3- (but not Stat1-) driven transcription (Zhang et al., 2003a), and to
suppress the growth of Src-transformed and Stat3-overexpressing murine broblasts (Lufei et al., 2003). Stat3 promotes cell
survival by transactivating a large array of anti-apoptotic genes, and is constitutively activated in a variety of pre-malignant
and malignant lesions (Buettner et al., 2002). The discovery of somatic and germline mutations that affect the GRIM-19-
encoding gene (ndufa13) in different types of human cancers has formally assigned GRIM-19 to the group of tumor suppres-
sors (Fusco et al., 2005; Maximo et al., 2005). Of note, GRIM-19 acts as a tumor suppressor not only by inhibiting Stat3, but
also by modulating other mitochondrial and extramitochondrial processes that are involved in tumorigenesis (see below).
Finally, as demonstrated by the generation of ndufa13
/
mice, GRIM-19 is essential for early embryonic development
due to its crucial role in the assembly and function of the respiratory chain complex I (Huang et al., 2004; Lu and Cao,
2008). Thus, GRIM-19 provides an interesting example of how mitochondria can be involved in self-sufcient growth signal-
ing (as well as in other features, see below) of cancer cells.
Constitutive NF-jB activation is common to different types of hematopoietic and solid malignancies. Depending on the
cell type and NF-jB-activating stimulus, members of the NF-jB family can orchestrate transcriptional programs affecting
processes as diverse as proliferation, differentiation, inammation, angiogenesis and cell death (Van Waes, 2007). Although
the NF-jB system is most frequently implicated in tumorigenesis by virtue of its anti-apoptotic effects (see below), several
studies indicate that NF-jB may also promote the emancipation of cancer cells from extrinsic growth signals. The promoter
region of multiple genes that control cell cycle progression (e.g., ccnb1, ccnd1, ccne1, coding for cyclin B1, D1 and E1, respec-
tively) contain NF-jB-responsive elements. Moreover, NF-jB has been shown to mediate the proliferation of glioblastoma
cells triggered by platelet-derived growth factor (PDGF) (Smith et al., 2008), thereby acting de facto as an effector of growth
signaling cascades. The NF-jB system and mitochondria are interconnected at multiple levels. To mention a few examples: a
pool of NF-jB is localized to the IMS thanks to the interaction between IjBa (inhibitor of jB a subunit) and ANT (Bottero
et al., 2001); NF-jB can be activated by mitochondrial stress-induced alterations of Ca
2+
homeostasis, which results in nu-
clear gene expression and phenotypic modications (Biswas et al., 2005); and, in multiple experimental settings, NF-jB-
dependent gene transactivation requires mitochondrial ROS (Hughes et al., 2005; Lluis et al., 2007). Finally, mitochondrial
ROS have been suggested to mediate estrogen-induced cell cycle progression by activating NF-jB (and other transcription
factors) (Felty and Roy, 2005), which points to the existence of a specic functional interplay between mitochondria and
NF-jB-dependent proliferation. Intriguingly, both mitochondrial uncoupling and mtDNA depletion have been shown to acti-
vate NF-jB via a specic pathway that involves calcineurin and the IjB kinase b subunit (IjKb), suggesting that mitochon-
dria employ preferential mechanisms to propagate signals of stress to the NF-jB system (Biswas et al., 2005, 2008).
Several proteins that are known to transduce growth signals, such as members of the mitogen-activated protein kinase
(MAPK) family, have been shown to localize to mitochondria and to regulate tumorigenesis-related processes including
mitophagy (see above) (Dagda et al., 2008) and steroidogenesis (see below) (Poderoso et al., 2008). Moreover, the subcellular
localization of MAPK family members reportedly affects the sensitivity of cancer cells to antiproliferative signals (see below)
(Galli et al., 2008). Altogether, these examples suggest that the interplay between components of multiple growth signaling
cascades and mitochondria may have tumorigenic outcomes, either by providing cells with self-sufcient proliferative stim-
uli or by modulating mitochondrial processes that are linked to oncogenesis and/or tumor progression.
3.3. Insensitivity to antiproliferative signals
Nonmalignant cells exposed to adverse conditions (e.g., chemotherapeutic agents) or intrinsic stress (e.g., oncogenic
stress) normally block the advancement of their cell cycle and activate mechanisms of repair and adaptation to stress. If cells
fail to recover, the cell cycle arrest becomes permanent (senescence) and may nally, after a latency period, trigger cell death
(Campisi and dAdda di Fagagna, 2007). A plethora of human cancers are characterized by the genetic and/or epigenetic inac-
tivation of cell cycle arresting proteins, including (but not limited to) p14
ARF
, p16
INK4a
, p21
Cip1
, p27
Kip1
and pRb (Baur et al.,
1999; Nakamura et al., 2001), thereby becoming insensitive to extrinsic/intrinsic antiproliferative signals.
Manganese superoxide dismutase (MnSOD), which catalyzes the transformation of superoxide to molecular oxygen (O
2
)
and hydrogen peroxide (H
2
O
2
), represents (one of) the major antioxidant enzyme in mitochondria. MnSOD is encoded by a
nuclear gene mapping to locus 6q25.3, and its function is often lost in tumor cells due to deletions and/or point mutations
(Foulkes et al., 1993; Re et al., 2003). The overexpression of catalytically active MnSOD reportedly inhibits the proliferation of
a wide variety of cancer types (Oberley, 2005), strongly pointing to MnSOD as a (mitochondrial) tumor suppressor protein.
However, the precise molecular mechanisms that underlie MnSOD-dependent cell cycle control have not yet been eluci-
dated, and contrasting observations have been published. While in some normal and immortalized cell lines the overexpres-
sion of MnSOD led to the transactivation of p21 (Zhong et al., 2004; Sarsour et al., 2005), in other experimental settings
MnSOD triggered senescence though a p21-independent pathway (Takada et al., 2002; Behrend et al., 2005). Steady-state
levels of H
2
O
2
reportedly inhibit cell growth by controlling the activation status as well as the mitochondrio-nuclear redis-
tribution of multiple members of the MAPK family (i.e., ERK1/2, p38, JNK1/2) (Galli et al., 2008). Irrespective of the above-
mentioned controversy, these observations suggest that the absence of MnSOD might contribute to tumorigenesis by
favoring the insensitivity of cancer cells to antiproliferative signals, most likely via indirect redox circuitries. In line with this
hypothesis, high levels of MnSOD have been associated with poor survival in multiple malignancies including glioblastoma
(Ria et al., 2001), gastric cancer (Kim et al., 2002) and colorectal carcinoma (Nozoe et al., 2003).
An intriguing link between the mitochondrial ssion/fusion machinery and senescence has recently been pointed out (Lee
et al., 2007). In particular, RNAi-mediated depletion of the mitochondrial protein FIS1 (which is required for ssion due to its
ability to recruit the mitochondrial membrane segregating factor DRP1) (Perfettini et al., 2005), has been shown to induce
the appearance of morphological and biochemical hallmarks of senescence, which could be prevented by the concomitant
depletion of OPA1, a component of the apparatus for mitochondrial fusion (Lee et al., 2007). Moreover, high nuclear levels
of DRP1 have been associated with increased chemoresistance and poor prognosis in lung cancer (Chiang et al., 2009). Taken
together, these observations suggest that the expression levels and subcellular distribution of proteins that regulate mito-
chondrial dynamics may affect tumorigenesis by favoring immortalization and chemoresistance.
3.4. Disabled cell death
As mitochondria occupy a central position in multiple subroutines of cell death (including but not limited to intrinsic/
extrinsic apoptosis and necrosis) (Kroemer et al., 2009) and as cancer cells are more resistant to death induction than their
normal counterparts, it is not surprising that numerous proteins localized to (or directly interacting with) mitochondria may
exert important roles in oncosuppression, oncogenesis, tumor progression and chemotherapy resistance. So far, dozens if not
hundreds of molecular pathways that link the mitochondrial control of cell death to malignant transformation have been
characterized (Ferri and Kroemer, 2001; Green and Kroemer, 2004). The precise description of these biochemical mecha-
nisms largely exceeds the scope of the present article (for a review see (Kroemer et al., 2007)). Here, we will list a few protein
families that are particularly relevant for the mitochondrial control of cell death in tumors.
The function of several pro-apoptotic proteins from the Bcl-2 family is lost via genetic and/or epigenetic mechanisms in a
wide variety of human cancers. This applies to both multidomain (e.g., Bax, Bak) and BH3-only (e.g., Bid, Bad) pro-apoptotic
members of the Bcl-2 family (Gutierrez et al., 1999; Sakuragi et al., 2002; Sturm et al., 2006). As an alternative, tumor cells
overexpress anti-apoptotic Bcl-2-like proteins (e.g., Bcl-2, Bcl-X
L
, Mcl-1) (Sakuragi et al., 2002; Rassidakis et al., 2003). This
can derive from a variety of mechanisms including transcriptional upregulation, gene amplication and reciprocal translo-
cation. The bcl-2 gene itself has been rst identied due to its overexpression in B-cell follicular lymphoma (Pegoraro et al.,
1984). This resulted from a reciprocal chromosomal translocation (t14:18) that placed the Bcl-2 coding sequence in frame
under the control of the immunoglobulin heavy chain promoter (Pegoraro et al., 1984).
The backbone components and interactors of the PTPC function at the crossroad between cell death regulation and bio-
energetic metabolism, and some of them exhibit altered expression or function in pre-malignant and malignant lesions
(Brenner and Grimm, 2006). Among others, this applies to: ANT1, which is highly expressed in terminally differentiated tis-
sues but poorly in highly proliferating (cancer) cells (Jang et al., 2008); ANT2, which is up-regulated in several hormone-
dependent malignancies (Le Bras et al., 2006); hexokinase 2 (HK2), which may determine the high glycolytic phenotype that
characterizes many cancers known as the Warburg effect (see below) (Pedersen et al., 2002; Rho et al., 2007); peripheral
benzodiazepine receptor (PBR, also known as TSPO, i.e., translocator protein of 18 kDa), which is implicated in cholesterol
metabolism and whose overexpression has been shown to correlate with aggressive phenotype in breast, colorectal and
prostate cancer (Papadopoulos, 2003); and mitochondrial creatine kinase (mtCK), which may exert tumor suppressing func-
tions in oral squamous cell carcinoma (Onda et al., 2006). Specic VDAC isoforms are known to control mitochondrial cell
death by acting either as pro-death (e.g., VDAC1) (Shimizu et al., 2000, 2001) or pro-survival (e.g., VDAC2) (Chandra et al.,
2005) modulators. However, mutation or altered expression of VDAC has not been formally demonstrated in human cancer
(Torres-Cabala et al., 2006; Rho et al., 2007). Whether this reects the existence of multiple VDAC isoforms and/or of proteins
that may substitute for VDAC during tumorigenesis remains to be determined (Baines et al., 2007; Galluzzi and Kroemer,
2007).
Upon MMP, the translocation of IMS proteins from mitochondria to the cytoplasmactivates the caspase cascade as well as
caspaseindependent cell death mechanisms (Kroemer et al., 2007). However, as demonstrated by gene knockout studies,
most IMS proteins contribute to cellular homeostasis and survival as they are present in mitochondria (Galluzzi et al.,
2008a). It is therefore not surprising that the levels of some IMS proteins are increased in specic tumor types (e.g., AIF
and EndoG in colorectal and gastric carcinomas) (Lee et al., 2006; Yoo et al., 2008) and decreased in others (e.g., AIF in acute
myeloid leukemia (AML) and EndoG in hepatocellular carcinoma) (Hess et al., 2007; Ahn et al., 2008). This presumably re-
ects the fact that the relative contribution of each IMS protein to pro-survival and pro-death mechanisms may be highly
variable in different tissues. In AML patients, reduced expression of AIF has a negative prognostic impact (Hess et al.,
2007), underscoring the general importance of the mitochondrial cell death pathway for the pathophysiology of this devas-
tating disease (Del Poeta et al., 2008).
A nal example of the multifaceted relationship between disabled cell death and mitochondria in tumor cells is provided
by p53, which is mutated and/or inactivated by epigenetic mechanisms in more than 50% of all human cancers (Vousden and
Lane, 2007). p53 has rst been characterized for its ability to accumulate upon stress and to orchestrate the transactivation
of pro-apoptotic (e.g., Bax, Puma), cell-cycle arresting (e.g., p21
Cip1
), and autophagy-inducing (e.g., DRAM) proteins (Vogel-
stein et al., 2000; Vousden and Lane, 2007). However, p53 has recently been found to exert a plethora of extranuclear activ-
ities. In particular, p53 can trigger MMP by physically interacting with Bcl-2 family proteins (Galluzzi et al., 2008c; Morselli
et al., 2008a), meaning that the cytoplasmic pool of p53 can cooperate with its nuclear counterpart in the activation of apop-
totic programs. Moreover, cytoplasmic p53 inhibits autophagy (Morselli et al., 2008b; Tasdemir et al., 2008), thereby sub-
verting the mechanism that removes damaged mitochondria, and as a consequence further reducing the threshold at
which MMP causes cell death.
Dozens, if not hundreds, of cancer-associated p53 mutations have been identied so far, each of which results in specic
functional changes at the protein level (Soussi, 2007). Several mutations that disrupt the capacity of the p53 protein to bind
DNA also affect its interaction with Bcl-2 family proteins (Moll et al., 2005; Tomita et al., 2006), suggesting that such muta-
tions can act as dual hits and abolish both the nuclear and the extranuclear functions of p53.
4. Angiogenesis, invasiveness, metastatic potential and mitochondria
As solid tumors proliferate, cells that are localized in the lesion core are confronted with unfavorable environmental con-
ditions, including low levels of oxygen and glucose. The response to hypoxic and metabolic stress is orchestrated by the tran-
scription factor hypoxia-inducing factor 1 (HIF-1), which is composed by a constitutive (b) and an oxygen-sensitive (a)
subunit (Semenza, 2007). HIF-1 transactivates a consistent number of genes whose products are implicated in metabolism
(e.g., pyruvate dehydrogenase kinase 1, PDK1, see below) and angiogenesis (e.g., vascularendothelial growth factor 1, VEGF-
1) (Hirota and Semenza, 2006; Pouyssegur et al., 2006). The most prominent pathway for HIF-1 activation requires mito-
chondrial ROS, and reportedly depends on the presence and function of the respiratory complex III (Klimova and Chandel,
2008). HIF-1 regulation is altered by genetic and/or epigenetic mechanisms in many types of human cancer (Pouyssegur
et al., 2006). Recently, a chemical library screen has lead to the identication of alkyliminophenylacetate compounds that
potently inhibit HIF-1-dependent transcription (Lin et al., 2008). These agents as well as nonalkyliminophenylacetate
HIF-1 inhibitors identied were found to block mitochondrial ROS generation, further highlighting the essential role of mito-
chondria in the HIF-1 mediated response to hypoxic stress (Lin et al., 2008). By favoring the loss of E-cadherin, HIF-1 also
promotes the so-called epithelialmesenchymal transition (EMT), which is a prerequisite for the metastatic behavior of solid
tumors (see below) (Esteban et al., 2006; Pouyssegur et al., 2006). Both endothelial and tumor cells ectopically express the
mitochondrial F
1
F
O
-ATP synthase at the cell surface, where it may contribute to angiogenesis by favoring extracellular acid-
ication (Chi et al., 2007). Inhibition of the F
1
F
O
-ATP synthase at the plasma membrane by endogenous angiostatin or by a
specic antibody has been associated with intracellular acidication that correlated with anti-angiogenic effects (Chi et al.,
2007).
Invasion and metastasis require dramatic biochemical modications including cytoskeletal rearrangements, loss of inte-
grin-dependent and -independent anchorage, enhanced motility and degradation of the extracellular matrix (ECM) (Joyce
and Pollard, 2009; Nguyen et al., 2009). Normal cells that detach from the basal membrane activate a cell death mechanism
known as anoikis, which is mostly mediated by apoptotic executioners (Simpson et al., 2008). Thus, disabled cell death (see
above) not only promotes early tumorigenesis and chemotherapy resistance, but also sustains the invasive/metastatic atti-
tude of tumor cells. However, this is not the sole link between mitochondria and the invasive/metastatic attitude of cancer
cells. Mitochondrial and extramitochondrial ROS deeply affect integrin signaling (Svineng et al., 2008), as well as the expres-
sion and activation of matrix metalloproteinases (Nelson and Melendez, 2004; Kumar et al., 2008). According to one recent
report, ROS would also favor the upregulation of CXCL14, a chemokine that promotes cell motility by binding to the inositol
1,4,5-trisphosphate receptor (IP
3
R) on the ER and hence elevating cytosolic Ca
2+
(Pelicano et al., 2009). Gene expression ar-
rays have demonstrated that oxidative phosphorylation-impaired osteosarcoma cells exhibit an altered expression of several
extracellular matrix remodeling factors including, but not limited to, metalloproteinases and their tissue inhibitors (van
Waveren et al., 2006). In non-small cell lung cancer A549 cells, partial mtDNA depletion and treatment with mitochondrial
inhibitors reportedly induce an invasive phenotype characterized by the upregulation of cathepsin L and transforming
growth factor b (TGFb), increased cytosolic Ca
2+
concentrations, and consequent activation of calcineurin and Ca
2+
-depen-
dent MAPK kinases (Amuthan et al., 2002). In liver metastases of colorectal cancer, the a and d subunits of the mitochondrial
F
1
F
O
-ATP synthase are expressed at higher levels than in primary tumors, and siRNA-mediated downregulation of these pro-
teins could decrease the in vitro invasiveness of human colon cancer cells (Chang et al., 2007). Of note, GRIM-19 has been
shown to inhibit V-Src-induced cell motility by preventing the cytoskeletal rearrangements that are required for podosome
formation, thereby exerting oncosuppressing functions also via Stat3-independent mechanisms (see above) (Sun et al.,
2009). Smac/DIABLO reportedly inhibits motility and migration of SH-EP neuroblastoma cells in the absence of any pro-
apoptotic stimulus (Vogler et al., 2005). Moreover, in colorectal cancer patients, the expression levels of Smac/DIABLO inver-
sely correlate with the incidence of metastasis and survival, pointing to Smac/DIABLO as a valuable independent prognostic
factor, at least in some clinical settings (Endo et al., 2009). Altogether, these examples support the notion that mitochondrial
alterations contribute to the angiogenetic, invasive and metastatic behavior of cancer cells.
5. Avoidance of the immune response and mitochondria
During the last decade, great attention has been paid to the role of the immune system in the control of tumorigenesis. In
particular, there is growing consensus on the fact that malignant transformation is associated with an acquired capacity of
live (and dying) cancer cells to avoid the immune response (Zitvogel et al., 2008).
The Bcl-2 family members Bax and Bak do not only play a critical role in the regulation of mitochondrial apoptosis (see
above) (Kroemer et al., 2007), but also participate in the molecular machinery that allow for the exposure of the ER-sessile
protein calreticulin (CRT) on the plasma membrane of dying tumor cells (Panaretakis et al., 2009). Some chemotherapeutic
agents (including anthracyclins and ionizing irradiation) are particularly effective in killing cancer cells while triggering CRT
exposure, which is required for the elicitation of a protective anticancer immune response in vivo (Obeid et al., 2007). Re-
cently, the molecular pathway that mediates pre-apoptotic CRT exposure has been shown to include an apoptotic module
that relies on the essential contribution of Bax, Bak and caspase-8 (Panaretakis et al., 2009). This apoptotic module would
operate downstream of an ER stress response that is necessary (but not sufcient) to elicit the immune response against
anthracyclin-treated tumor cells. Accordingly, depletion of Bax and Bak (as well as of caspase-8 and several additional pro-
teins that participate in the ER stress response) abolished CRT exposure induced by anthracyclins, thereby reducing the
immunogenicity of dying cancer cells injected into mice (Panaretakis et al., 2009). At present it is not known whether
Bax and Bak contribute to CRT exposure by virtue of their capacity to regulate Ca
2+
uxes (Scorrano et al., 2003), which
are required for CRT exposure (Tu et al., 2008), or whether they operate at the level of mitochondria. Irrespective of this
open question, the inactivation the Bax/Bak system may provide tumors with a dual advantage (i) by reducing the number
of cancer cells succumbing to therapeutic regimens, and (ii) by blocking CRT exposure and thus inhibiting the anticancer im-
mune response elicited by dying tumor cells (Zitvogel et al., 2008).
Mitochondrial and extra-mitochondrial members of the HSP family (e.g., HSP70) exposed at the cell surface or released by
dying cancer cells transduce an endogenous danger signal that can increase the immunogenicity of tumors (Jeannin et al.,
2008). Nevertheless, HSPs are often upregulated in malignant cells, likewise because most of these proteins confer relevant
cytoprotection in response to adverse conditions including oxygen/glucose shortage, oxidative stress and chemotherapy
(Calderwood and Ciocca, 2008). Thus, high HSP levels may exert bona de oncogenic functions by protecting cancer cells
from stress, while at the same time exposing tumors to more intense immune responses. The fact that (at least in specic
cases) the expression levels of some HSP (e.g., HSP20) inversely correlate with tumor stage indicates that the immunogenic
function of selected HSPs may be more important than their cytoprotective roles during the selection process that occur
throughout tumor progression (Noda et al., 2007).
6. Metabolic reprogramming and mitochondria
The most impressive metabolic alteration of cancer cells consists in the so-called Warburg phenomenon, that is an in-
creased ow through glycolysis in spite of high oxygen tension (aerobic glycolysis), which leads to enhanced lactate gener-
ation (Brahimi-Horn et al., 2007). The Warburg phenomenon arises from both mitochondrial and extra-mitochondrial
alterations, and it is sufciently diffuse among different types of cancer that it is exploited for clinical tumor imaging by
means of a glucose derivative coupled to positron emission tomography (PET) (Mankoff et al., 2007). Besides the Warburg
effect, most tumors present extensive metabolic reprogramming, which frequently implicates mitochondria. The mecha-
nisms that account for such alterations are deeply intertwined (Kroemer and Pouyssegur, 2008), and their description is be-
yond the aim of the present review. Intriguingly, most molecular changes that favor oncogenesis also have a direct or indirect
metabolic outcome. Here, a few examples will be provided to highlight the critical contribution of mitochondria to yet an-
other feature of tumor cells.
Often, mitochondria from tumor cells are relatively small, present evident ultrastructural alterations, are decient in the
b-F
1
ATP synthase subunit, and are characterized by an increased Dw
m
(Kim et al., 2007; Lopez-Rios et al., 2007), altogether
pointing to primary defects in the respiratory chain that may contribute to aerobic glycolysis. Impaired oxidative phosphor-
ylation favoring the Warburg phenomenon may result from several oncogenic mechanisms. Defects in the p53 system lead
to impaired transactivation of SCO2, a mitochondrial protein required for the assembly of cytochrome c oxidase (Matoba
et al., 2006), and of TIGAR, an isoform of 6-phosphofructo-2-kinase (PFK2) whose expression reportedly inhibits ROS gener-
ation, thereby exerting tumor suppressive functions (Bensaad et al., 2006). Constitutive activation of phosphatidylinositol-3
kinase (PI3K) leads to the transcriptional repression of carnitine palmitoyltransferase 1A, an enzyme of the OM that normally
initiates the mitochondrial import of fatty acids destined to b-oxidation (Deberardinis et al., 2006). HIF-1 is often hyperac-
tivated in cancer cells (see above) and controls the transcription of pyruvate dehydrogenase kinase 1 (PDK1) (Kim et al.,
2006). PDK1-dependent inhibition of pyruvate dehydrogenase (PDH) results in decreased conversion of pyruvate to acet-
yl-CoA, which represents the rate-limiting reaction of the tricarboxylic acid (TCA) cycle, and hence decient oxidative phos-
phorylation (Papandreou et al., 2006). Pharmacological PDK1 inhibition with dichloroacetate (DCA, a metabolic modulator
used for decades in humans to treat lactic acidosis) reportedly reactivates PDH and corrects mitochondrial hyperpolarization,
thereby triggering apoptosis in several tumor cell lines (Bonnet et al., 2007). Intriguingly, tumorigenic germline mutations of
two TCA cycle enzymes (i.e., fumarate hydratase, FH, and succinate dehydrogenase, SDH) promote HIF-1 induction via the
accumulation of intermediate metabolites (i.e., fumarate and succinate) that inhibit the oxygen-dependent pathway that
normally targets HIF-1a to degradation (Gottlieb and Tomlinson, 2005).
In malignant cells, both HK1 and HK2 are more tightly associated with VDAC at the OM than in normal cells, which allows
them to gain direct access to mitochondrial ATP exported into the cytosol (Pastorino et al., 2005) Increased HK/VDAC binding
may result from constitutive signaling through the PI3K-Akt axis by at least two distinct mechanisms. First, the interaction of
HK2 with mitochondria is enhanced by direct Akt-dependent HK2 phosphorylation (Miyamoto et al., 2008). Second, Akt may
interfere with the GSK3b-dependent phosphorylation of VDAC, which reportedly disrupts the HK2/VDAC interaction
(Pastorino et al., 2005). In tumor cells characterized by inefcient oxidative phosphorylation, VDAC-bound HK may couple
residual ATP production in mitochondria with the rate-limiting step of glycolysis, thereby providing the basis for the
Warburg phenomenon. Mitochondrially-bound HK inhibits MMP, presumably by interfering with the opening of the PTPC
(which also involves VDAC) (Abu-Hamad et al., 2008). In line with this notion, peptides (Chiara et al., 2008) as well as small
molecules (Galluzzi et al., 2008b; Goldin et al., 2008) that disrupt the interaction between HK and mitochondria can selec-
tively kill tumor cells, both in vitro and in vivo. Intriguingly, recent work suggests that the detachment of HK2 from mito-
chondria would trigger PTPC-dependent MMP independently of VDAC (Chiara et al., 2008), consistent with the notion
that VDAC is dispensable for MMP in several models of cell death (Galluzzi and Kroemer, 2007).
A generalized increase in anabolism characterizes nearly all cancer types (Kroemer and Pouyssegur, 2008). Sustained sig-
naling though the anabolic PI3K-Akt axis enhances fatty acid biosynthesis and steroidogenesis through the activation of ATP
citrate lyase (ACL), the cytosolic enzyme that catalyzes the ATP-dependent cleavage of citrate into acetyl-CoA and oxalace-
tate (Manning and Cantley, 2007), and by transactivating fatty acid synthase (FASN), which is upregulated in many cancers
(Wang et al., 2005). PBR, one of the putative components of the PTPC (see above), controls the rate-limiting step of steroi-
dogenesis by regulating cholesterol transport from the OM to the IM (Papadopoulos, 2003), and is overexpressed in numer-
ous hormone-dependent and independent cancers. In line with the notion that membrane biogenesis (which requires
cholesterol) is considerably increased in highly proliferating cells, PBR overexpression has been found to correlate with
the aggressive phenotype of breast, colorectal and prostate cancer (Hardwick et al., 1999; Papadopoulos, 2003). Finally,
oncogenic tyrosine kinases can stimulate anabolic reactions in cancer cells by partially inhibiting the cancer-specic isoform
of pyruvate kinase PKM2, which catalyzes the last step of glycolysis leading to pyruvate (Christofk et al., 2008). In conditions
of elevated glycolytic ux, this would result in the deviation of metabolic intermediates toward anabolic reactions, and
concomitantly avoid an excessive production of pyruvate.
As it stands, mitochondrial alterations lying at the crossroad between metabolism and cell death regulation represent
promising targets for the development of novel therapies for the treatment of cancer. Molecules that simultaneously revert
the hyperglycolytic state of malignant cells and sensitize them to death induction may turn out to be particularly efcient
anticancer drugs. DCA and HK-targeted strategies have provided a rst proof-of-principle for this approach.
7. Concluding remarks
As discussed above, a wide array of human malignancies share molecular alterations that directly or indirectly linked to
mitochondria (Fig. 3, Table 1). Since mitochondria occupy at a strategic position between bioenergetic/biosynthetic metab-
olism and cell death regulation, they are emerging as privileged targets for the development of novel chemotherapeutic
agents (Gogvadze et al., 2008). During the last decade, numerous approaches that selectively target cancer cells by virtue
of their mitochondrial defects have been shown to exert antitumor effects (Galluzzi et al., 2006). These include, but are
not limited to: (i) mitochondriotoxic agents that preferentially accumulate in cancer cells due to mitochondrial hyperpolar-
ization (e.g., F16) (Fantin et al., 2002); (ii) pharmacological modulators of the Bcl-2 protein family (e.g., ABT-737, HA14-1)
(Manero et al., 2006; Mason et al., 2008); (iii) compounds that bind to putative PTPC subunits (e.g., PK11195) (Decaudin
Fig. 3. Mitochondrial gateways to cancer. Most if not all the common features of cancer cells, as rst proposed by Hanahan and Weinberg (2000) and later by
Kroemer and Pouyssegur (2008), Zitvogel et al. (2008), and Morselli et al. (2009), implicate either directly or in an indirect fashion mitochondria. Thus,
mitochondria represent promising targets for the development of novel anticancer strategies. In this context, the most valuable compounds would be those
that simultaneously hit multiple mitochondrial processes, thereby mimicking the efcacy of combination therapies yet presenting the side effects of a
single agent. Please refer to the text for further details. HIF-1, hypoxia-inducing factor 1; MnSOD, manganese superoxide dismutase; PBR, peripheral
benzodiazepine receptor; PDK1, pyruvate dehydrogenase kinase 1.
Table 1
Examples of the multifaceted implication of mitochondria in cancer.
Protein/process Localization Physiological function(s) Implication(s) in cancer References
AIF IMS Upon MMP, goes to the nucleus and
mediate DNA degradation
Required for the assembly/maintenance of
complex I
Overexpressed in gastric
carcinoma cells as
compared to normal
mucosal cells
Low expression is a negative
prognostic factor in AML
Lee et al. (2006), Kroemer
et al. (2007), Hess et al.
(2007), Galluzzi et al.
(2008a)
ANTs IM Backbone PTPC subunits
Normally mediate the exchange of
adenine nucleotides across IM
ANT1 is downregulated in
highly proliferating (cancer)
cells
ANT2 is anti-apoptotic and
upregulated in many
cancers
Le Bras et al. (2006), Jang
et al. (2008)
Bak/Bax Cytoplasm
OM
Promote MMP and cell death by multiple
mechanisms
Required for CRT exposure on the surface
of dying cancer cells
Inactivated/lost in several
types of human cancer
Gutierrez et al. (1999),
Sakuragi et al. (2002),
Kroemer et al. (2007)
Bcl-2/Bcl-X
L
ER
OM
Block MMP, thereby enhancing the
resistance of cancer cells to a plethora of
cell death inducers
Overexpressed in many
hematopoietic cancers, due
to amplication or
translocation
Rassidakis et al. (2003),
BH3-only proteins Cytoplasm
Cytoskeleton
OM
Sense stress and activate cell death-
inducing mechanisms
Inactivated/lost in several
types of human cancer
Sturm et al. (2006), Kroemer
et al. (2007)
CPT1A OM Initiates the mitochondrial import of fatty
acids destined to b-oxidation
Repressed by constitutive
PI3K activation, which
favors the Warburg
phenomenon
Deberardinis et al. (2006)
Dw
m
IM Required for mitochondrial ATP synthesis
via F
1
F
O
-ATP synthase
Many types of cancers
exhibit increased Dw
m
,
often coupled to inefcient
OXPHOS
Kim et al. (2007), Lopez-
Rios et al. (2007)
DRP1 Cytoplasm
Mitochondria
Nucleus
Required for mitochondrial membrane
segregation during mitochondrial ssion
Elevated nuclear expression
of DRP1 has been associated
with poor prognosis in lung
cancer
Chiang et al. (2009)
EndoG IMS Upon MMP, goes to the nucleus and
mediate DNA degradation
Involved in recombination-dependent
DNA repair
Altered expression in
human tumors of distinct
origin
Required for the survival of
tetraploid colon cancer cells
Ahn et al. (2008), Galluzzi
et al. (2008a), Yoo et al.
(2008)
F
1
F
O
-ATP synthase IM Normally ensures mitochondrial ATP
synthesis driven by Dw
m
Favor extracellular acidication, thereby
promoting angiogenesis; inhibited by the
endogenous anti-angiogenic factor
angiostatin
Overexpressed in colorectal
cancer metastatic lesions as
compared to primary
tumors
Ectopically expressed at the
plasma membrane surface
in endothelial and tumor
cells
Chang et al. (2007), Chi et al.
(2007)
Fatty acid
biosynthesis
Cytoplasm
Mitochondria
Supplies cells with fatty acids Enhanced in cancer cells by
PI3K-dependent activation
of ACL and FASN
Manning and Cantley
(2007), Wang et al. (2005)
FIS1 OM Recruits Drp1, required for mitochondrial
ssion
Prevents senescence Lee et al. (2007)
GRIM-19 Mitochondria Sequesters and inhibits Stat3
Prevents cytoskeletal rearrangements
required for podosome formation
Required for complex I assembly
Mutated in a wide array of
human neoplasms
Lufei et al. (2003), Zhang
et al. (2003a), Fusco et al.
(2005), Maximo et al.
(2005), Sun et al. (2009)
HIF-1 Nucleus Controls the transcription of genes
implicated in invasion, angiogenesis and
metabolism
HIF-1 activation requires ROS, and
depends on complex III
Deregulated by a plethora of
molecular mechanisms in
several types of cancer
Hirota and Semenza (2006),
Pouyssegur et al. (2006),
Klimova and Chandel
(2008)
(continued on next page)
Table 1 (continued)
HKs Cytoplasm Catalyze the rst and rate-limiting step of
glycolysis
Putative PTPC subunits
In cancer cells, HKs are
tightly associated with
VDAC, in turn favoring the
Warburg effect
Pastorino et al. (2005),
Galluzzi et al. (2008b),
Miyamoto et al. (2008)
HSPs Cytoplasm
Mitochondria
Nucleus
Molecular chaperones that exert
cytoprotective effects in response to
adverse conditions
Exposed at the surface or released by
dying cancer cells
Upregulated in multiple
solid and hematological
tumors
HSP20 expression levels
inversely correlate with
hepatocellular tumor stage
Noda et al. (2007), Jeannin
et al. (2008), Calderwood
and Ciocca (2008)
hTERT Mitochondria
Nucleus
Sustains immortalization by preserving
telomere length
Binds to mtDNA and exerts MMP-
inhibitory effects
In vitro, depletion of hTERT
sensitizes cancer cells to
death, while hTERT
overexpression exerts
cytoprotective effects
Massard et al. (2006),
Santos et al. (2006), Xi et al.
(2006), Ahmed et al. (2008),
Haendeler et al. (2009)
MAPKs Cytoplasm
Mitochondria
Nucleus
Mediate several growth signaling cascades
converging on the activation of
transcription factors
From mitochondria, they
regulate tumorigenesis-
related processes and they
sustain insensitivity to
antiproliferative signals
Dagda et al. (2008), Galli
et al. (2008), Poderoso et al.
(2008)
Mitophagy Cytoplasm Impaired mitophagy promote ROS
generation
Autophagy/mitophagy-
relevant proteins are often
lost in cancer
Yue et al. (2003)
MnSOD Mitochondria Can trigger senescence via p21-dependent
or -independent mechanisms, presumably
by maintaining high H
2
O
2
levels
Inactivated by genetic or
epigenetic mechanisms in a
variety of tumors
High expression is a
negative prognostic factor
in glioblastoma, gastric and
colorectal cancer
Ria et al. (2001), Kim et al.
(2002), Nozoe et al. (2003),
Re et al. (2003), Zhong et al.
(2004), Behrend et al.
(2005), Sarsour et al. (2005)
Mortalin Cytoplasm
ER
Mitochondria
Binds to and inactivate p53
Inuences the Ras-Raf-MAPK signaling
pathway
Exerts antioxidant effects upon
phosphorylation by PINK1
Enhances tumorigenicity of
HEFs, in vivo
Negative prognostic factor
in colorectal cancer
Wadhwa et al. (2002,2003),
Dundas et al. (2005),
Wadhwa et al. (2006), Hua
et al. (2007), Pridgeon et al.
(2007)
NF-jB Cytoplasm
IMS
Nucleus
May promote malignancy in response to
mitochondrial stress
NF-jB activation requires mitochondrial
ROS
Constitutively activated in
multiple human tumors,
transduces pro-proliferative
and anti-apoptotic signals
Hughes et al. (2005)), Lluis
et al. (2007), Biswas et al.
(2005)
OXPHOS IM Generates the Dw
m
that is required for
ATP synthesis by F
1
F
O
-ATP synthase
Impaired in many human
cancers, in turn favoring the
Warburg effect
Brahimi-Horn et al. (2007),
Dasgupta et al. (2008),
Kroemer and Pouyssegur
(2008)
p53 Nucleus Master regulator of cell death, cell cycle
and autophagy
Controls the expression of multiple
enzymes implicated in bioenergetic/redox
metabolism
Inactivated by genetic and/
or epigenetic mechanisms
in more than 50% of human
cancers
Vogelstein et al. (2000),
Vousden and Lane (2007),
Galluzzi et al., 2008c),
Morselli et al. (2008a)
OM Directly promotes MMP
PBR OM Regulates cholesterol import from the OM
to the IM
Putative PTPC subunit
Overexpressed in hormone-
dependent cancers, which
correlates with malignancy
Hardwick et al. (1999),
Papadopoulos (2003),
PKM2 Cytoplasm Catalyzes the last step of glycolysis
leading to pyruvate generation
Inhibited by constitutively
active RTKs, resulting in the
deviation of glycolytic
intermediates to anabolic
pathways
Christofk et al. (2008)
PDK1 Mitochondria Normally inhibits PDH, resulting in
decreased conversion of pyruvate to
acetyl-CoA
Upregulated by HIF-1 in
cancer cells, thus promoting
the Warburg phenotype
Papandreou et al. (2006),
Bonnet et al. (2007)
ROS Cytoplasm
ECM
IM
Promote mutagenesis
Favor invasion/metastasis
Promote HIF-1 and NF-jB activation
Extra-mitochondrial
sources of ROS may also
contribute to oncogenesis
Nelson and Melendez
(2004), Zhou et al. (2007),
Kumar et al. (2008), Svineng
et al. (2008), Pelicano et al.
(2009)
Table 1 (continued)
SCO2 IM Required for COX assembly Underexpressed in p53-
decient cancer cells
Matoba et al. (2006)
Smac/DIABLO IMS Upon release into the cytosol, indirectly
promotes the activation of the caspase
cascade
Inhibits neuroblastoma cell
migration, in vitro
Expression levels inversely
correlate with survival in
colorectal cancer patients
Vogler et al. (2005),
Kroemer et al. (2007), Endo
et al. (2009)
TCA cycle Mitochondria Produces the reducing equivalents
required for OXPHOS
FH and SDH mutations
indirectly promote HIF-1
induction
Gottlieb and Tomlinson
(2005)
TIGAR Cytoplasm p53-regulated PFK2 isoform that reduces
ROS generation
Expression reduced in p53-
decient cancer cells
Bensaad et al. (2006)
VDACs OM Backbone PTPC subunits
Mediate the exchange of small
metabolites between the cytosol and the
mitochondrial matrix
VDAC1 is pro-apoptotic
VDAC2 is anti-apoptotic by
binding to/inhibiting Bak
Shimizu et al. (2000),
Shimizu et al. (2001),
Chandra et al. (2005)
Abbreviations: ACL, ATP citrate lyase; AML, acute myeloid leukemia; AIF, apoptosis inducing factor; ANTs, adenine nucleotide translocases; BH3, Bcl-2
homology domain; Dw
m
, mitochondrial transmembrane potential; COX, cytochrome c oxidase; CPT1A, carnitine palmitoyltransferase 1A; CRT, calreticulin;
DRP1, dynamin-related protein 1; ECM, extracelluar matrix; EndoG, endonuclease G; ER, endoplasmic reticulum; FASN, fatty acid synthase; FH, fumarate
hydratase; HEFs, human embryonic broblasts; HIF-1, hypoxia-inducible factor 1; HKs, hexokinases; HSP, heat-shock protein; hTERT, human telomerase
reverse transcriptase; IM, mitochondrial inner membrane; IMS, mitochondrial intermembrane space; MAPK, mitogen-activated protein kinase; MMP,
mitochondrial membrane permeabilization; MsSOD, manganese superoxide dismutase; OM, mitochondrial outer membrane; OXPHOS, oxidative phos-
phorylation; PBR, peripheral benzodiazepine receptor; PDH, pyruvate dehydrogenase; PDK1, PDH kinase 1; PFK2, 6-phosphofructo-2-kinase; PI3K, phos-
phatidyolinositol-3 kinase; PINK1, PTEN induced putative kinase 1; PKM2, M2 isoform of pyruvate kinase; PTPC, permeability transition pore complex; ROS,
reactive oxygen species; RTKs, receptor tyrosine kinases; SCO2, synthesis of cytochrome c oxidase 2; SDH, succinate dehydrogenase; TCA, tricarboxylic acid;
TIGAR, TP53-induced glycolysis and apoptosis regulator; VDACs, voltage-dependent anion channels.
Table 2
Examples of mitochondrially-targeted compounds with anticancer properties.
Agent Target/mode of action Antitumor activity References
Modulators of the Bcl-2 protein family
A-385358 Bcl-X
L
-specic inhibitor Synergized with paclitaxel in NSCLC
A549 cells xenograft models
Shoemaker et al. (2006)
ABT-263 Bcl-2, Bcl-X
L
and Bcl-w inhibitor Undergoing phase I/II clinical trials
for the therapy of solid and
hematological malignancies
(Tse et al. (2008), Kang and
Reynolds (2009)
ABT-737 Bcl-2, Bcl-X
L
and Mcl-1 inhibitor In vivo, in murine xenograft models of
lymphoma and glioblastoma
Oltersdorf et al. (2005), Kang and
Reynolds (2009)
AT-101 Bcl-2, Bcl-X
L
and Mcl-1 inhibitor Undergoing phase I/II clinical trials
for the treatment several solid
tumors
Tomillero and Moral (2008), Kang
and Reynolds (2009)
GX15-070 Mcl-1-specic inhibitor Undergoing phase I/II clinical trials
for the therapy of several solid and
hematological cancers
Nguyen et al. (2007), Kang and
Reynolds (2009)
HA14-1 Bcl-2 ligand In vitro, in multiple cancer cell lines,
and in vivo, in glioblastoma
xenografts
Manero et al. (2006)
Oblimersen sodium Bcl-2-specic antisense
oligonucleotide
Undergoing phase II/III clinical trials
for the treatment of melanoma, CLL
and NHL
Tomillero and Moral (2008), Kang
and Reynolds (2009)
SAHB peptide Direct Bax activator In vitro, in a panel of leukemic cell
lines and in vivo, in a murine model of
leukemia
Walensky et al. (2004), Gavathiotis
et al. (2008)
Lipophilic cationic agents
F16 Direct inducer of MPT In vitro, in a variety of mouse and
human tumor cell lines
Fantin et al. (2002), Fantin and
Leder (2004)
(KLAKKLAK)
2
peptide Exerts direct mitochondrion-
permeabilizing effects
In vitro, in KS and breast cancer cells
and in vivo, in models of breast
carcinoma
Ellerby et al. (1999)
(continued on next page)
et al., 2002); (iv) redox active agents that trigger cell death by provoking futile redox cycles in mitochondria (e.g., b-phen-
ylethyl isothiocyanate, arsenic trioxide) (Trachootham et al., 2006; Toogood, 2008); and retinoid-related molecules that in-
duce MPT independently of retinoid receptors (e.g., CD437, ST1926) (Marchetti et al., 1999; Fontana and Rishi, 2002;
Garattini et al., 2004) (Table 2). Hypothetically, the most efcient mitochondrially-targeted therapies would be those that
affect mitochondrial processes linked to several features of the neoplastic phenotype. As an example, compounds that dis-
rupt the interaction between HK and VDAC might display consistent antitumor effects by virtue of a dual effect: uncoupling
of aerobic glycolysis from residual ATP synthesis occurring in mitochondria and sensitization to PTPC-dependent cell death
(Goldin et al., 2008). Similar approaches may hit cancer cells though multiple simultaneous mechanisms, thereby acting de
facto as combination therapies while bringing about the side effects of single agents, with obvious benets. In conclusion, we
expect that the ever accumulating knowledge on tumor-associated mitochondrial defects will lead to the design of effective
Table 2 (continued)
Agent Target/mode of action Antitumor activity References
L-t-C6-Pyr-Cer Ceramide-derivative, accumulates in
mitochondria driven by Dw
m
In vitro and in vivo, in HNSCC cell
lines and xenografts
Senkal et al. (2006)
PTPC interactors
Clodronate Inhibitor of ANT-mediated ATP/ADP
exchange
Employed as an adjuvant treatment
for the reduction of skeletal
metastases
Lehenkari et al. (2002), Diel et al.
(2008)
FGIN-1-27 PBR ligand In vivo, in mice xenografted with
human HT29 colorectal cancer cells
Shoukrun et al. (2008)
Methyl jasmonate Disrupts the HK-VDAC interaction at
the OM
In vivo, in mouse models of leukemia,
melanoma and colorectal carcinoma
Galluzzi et al.(2008b), Goldin et al.,
2008)
PK11195 Acts both as a PBR ligand and via
PBR-independent pathways
In vitro, in multiple cancer cell lines,
and in vivo, in murine models of SCLC
Decaudin et al. (2002),Gonzalez-Polo
et al. (2005)
Redox-active agents
5-ALA Metabolized to the light-sensitive
ROS producer protoporphyrin IX
Currently used for PTD of pre-
cancerous actinic keratosis and some
types of skin lymphoma
Gupta and Ryder (2003)
Arsenite trioxide Triggers ROS overgeneration,
oxidative damage and MPT
Currently in use for the treatment of
PML and multiple myeloma
Chen et al. (1998), Larochette et al.
(1999), Toogood (2008)
Benzyl isothiocyanate Ignites ROS overgeneration by
inhibiting
complex III
In vivo, in models of leukemia and
pancreatic cancer
Sahu and Srivastava (2009), Tsou
et al. (in press)
PEITC Disables the glutathione system,
thereby triggering ROS overload
In vivo, in models of xenografted and
chemically-induced lung and
prostate cancer
Trachootham et al. (2006), Khor et al.
(2006)
Retinoid-related molecules
4-HPR Activates ROS-dependent MPT by
elevating ceramide levels
Undergoing phase I/II clinical trials
for the therapy of several solid and
hematological cancers
Hail and Lotan (2001), Lovat et al.
(2004)
ATRA Can bind ANT and hence trigger MPT
independently of RAR
Currently employed for the treatment
of promyelocytic leukemia
Notario et al. (2003)
Betulinic acid Triggers PTPC-dependent MPT In vivo, in mouse models of
melanoma and neuroectodermal
tumors
Fulda and Debatin (2000), Mullauer
et al. (2009)
CD437 Impairs Ca
2+
homeostasis, thereby
mediating MPT
In vivo, in murine models of APL,
melanoma and teratocarcinoma
Marchetti et al. (1999), Fontana and
Rishi (2002)
ST1926 Impairs Ca
2+
homeostasis, thereby
mediating MPT
Undergoing phase I clinical trials for
the treatment of leukemia
Garattini et al. (2004), Parrella et al.
(2006)
Abbreviations: 4-HPR, N-(4-hydroxyphenyl)retinamide; 5-ALA, 5-aminolevulinic acid; A-385358, 4-(3-dimethylamino-1-phenylsulfanylmethylpropyla-
mino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; ANT, adenine nucleotide translocase; APL, acute promyelocytic leukemia;
AT-101, R-()-gossypol acetic acid; ATRA, all-trans-retinoic acid; CD437, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid; CLL,
chronic lymphocytic leukemia, Dw
m
, mitochondrial transmembrane potential; FGIN-1-27, 2-aryl-3-indoleacetamide; GX15-070, obatoclax; HK, hexoki-
nase; HNSCC, head and neck squamous cell carcinoma; KS, Kaposis sarcoma; L-t-C6-Pyr-Cer, L-threo-C6-pyridinium-ceramide-bromide; MCL, mantle cell
lymphoma; MPT, mitochondrial permeability transition; NHL, non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer; OM, mitochondrial outer
membrane; PBR, peripheral benzodiazepine receptor; PEITC, b-phenylethyl isothiocyanate; PK11195, 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolin-
ecarboxamide; PML, promyelocytic leukemia; PTD, photodynamic therapy; PTPC, permeability transition pore complex; RAR, retinoic acid receptor; ROS,
reactive oxygen species; SAHB, stabilized alpha-helix of Bcl-2 domains; SCLC, small-cell lung cancer; ST1926 (E)-3-(4
0
-hydroxy-3
0
-adamantylbiphenyl-4-
yl)acrylic acid; VDAC, voltage-dependent anion channel.
anticancer therapies. On similar grounds, chemopreventive therapies might aim at closing the mitochondrial gateways to
neoplasia.
Acknowledgments
The authors declare no conicting nancial interests. This work was supported by grants from Ligue Nationale contre le
Cancer (LNC), Agence Nationale de Recherche (ANR), Agence Nationale de Recherches sur le SIDA (ANRS), Institut National du
Cancer (INCa), Cancrople Ile-de-France, Fondation pour la Recherche Mdicale (FRM), Sidaction and the European Com-
mission (Active p53, Apo-Sys, ApopTrain, TransDeath, RIGHT). O.K. is the recipient of an EMBO Ph.D. fellowship. E.M. is
funded by an ApopTrain Ph.D. student fellowship.
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