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Adenine Nucleotide Translocase Family: Four Isoforms for Apoptosis Modulation in Cancer

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Adenine Nucleotide Translocase Family: Four Isoforms for Apoptosis Modulation in Cancer Oncogene (2011) 30, 883–895 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer C Brenner1,2,3, K Subramaniam4, C Pertuiset1,2,3 and S Pervaiz4,5,6,7 1Univ Paris-Sud, Chaˆtenay-Malabry, France; 2INSERM UMR-S 769, Chaˆtenay-Malabry, France; 3PRES UniverSud Paris, Chaˆtenay-Malabry, France; 4Department of Physiology, Apoptosis, ROS and Cancer Biology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 5NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; 6Duke-NUS Graduate Medical School, Singapore and 7Singapore-MIT Alliance, Singapore Mitochondria have important functions in mammalian release of several pro-apoptotic factors including cyto- cells as the energy powerhouse and integrators of the chrome c, AIF, smac/DIABLO and caspases from the mitochondrial pathway of apoptosis. The adenine nucleo- intermembrane space to the cytosol. Collectively, these tide translocase (ANT) is a family of proteins involved in events contribute to the initiation of the final stages of cell death pathways that perform distinctly opposite cell death. MMP is currently considered as the point-of- functions to regulate cell fate decisions. On the one hand, no-return in the lethal cascade and a promising ANT catalyzes the adenosine triphosphate export from therapeutic target, as its pharmacological or genetic the mitochondrial matrix to the intermembrane space with inhibition prevents cell death under many circumstances the concomitant import of ADP from the intermembrane (Costantini et al., 2000b; Bouchier-Hayes et al., 2005; space to the matrix. On the other hand, during periods of Fulda et al., 2010). stress, ANT could function as a lethal pore and trigger the A number of pathological states, most prominent process of mitochondrial membrane permeabilization, being cancer, has been associated with or results from a which leads irreversibly to cell death. In human, ANT is mitochondrial dysfunction and impairment in MMP encoded by four homologous genes, whose expression induction. Mitochondria can contribute to oncogenesis is not only tissue specific, but also varies according to the through a variety of mechanisms, including mutations pathophysiological state of the cell. Recent evidence of nuclear or mtDNA-encoded mitochondrial tumor revealed a differential role of the ANT isoforms in suppressors, metabolite accumulation (for example apoptosis and a deregulation of their expression in cancer. succinate and fumarate), production of reactive oxygen In this review, we introduce the current knowledge of species (ROS), apoptosis resistance, hypoxia-like path- ANT in apoptosis and cancer cells and propose a novel way activation and bioenergetic dysfunction (Gottlieb classification of ANT isoforms. and Tomlinson, 2005). Thus, in certain tumor cells, the Oncogene (2011) 30, 883–895; doi:10.1038/onc.2010.501; decreased adenosine triphosphate (ATP) production published online 15 November 2010 through mitochondrial oxidative phosphorylation is balanced by an increased ATP synthesis by glycolysis Keywords: cancer; cell death; mitochondria; ADP/ATP to maintain a vital energetic homeostasis, as first carrier; mitochondrial membrane permeabilization described by Warburg et al. (1924) and Warburg (1956). However, non-Warburg tumor cells in which oxydative phosphorylation is used primarily to generate Introduction ATP rather than glycolysis have also been previously described, notably in gliomas cells (Bouzier et al., 1998; Mitochondria have important functions in mammalian Beckner et al., 2005; Griguer et al., 2007; Rodrı´guez- cells, such as serving the energy powerhouse and Enrı´quez et al., 2010). Among the proteins responsible integrators of the intrinsic pathway of apoptosis for mitochondrial dysfunction in cancer, the mito- (Kroemer et al., 1998, 2007; Desagher and Martinou, chondrial adenine nucleotide translocase (ANT) or 2000). Apoptosis implies the translocation or the ADP/ATP carrier has been suggested to have an association of cellular proteins to the membrane of important function (Faure Vigny et al., 1996; Halestrap mitochondria, such as proteins triggering the mito- and Brenner, 2003; Chevrollier et al., 2005a; Brenner chondrial membrane permeabilization (MMP) and the and Grimm, 2006). ANT is an integral protein inserted into the mito- chondrial inner membrane (IM) through six transmem- Correspondence: Dr C Brenner, INSERM UMR-S 769, Faculte´de brane helices as revealed by 3D-structure analysis Pharmacie, Univ Paris-Sud 5, Rue J.-B. Cle´ment, Chaˆtenay-Malabry (Pebay-Peyroula et al., 2003). Its structure is similar to Cedex F-92290, France. E-mail: [email protected] that predicted for other mitochondrial carriers and then Received 30 July 2010; revised 22 September 2010; accepted 25 allows the electrogenic exchange of two substrates, September 2010; published online 15 November 2010 namely ADP and ATP, between the matrix and the ANT isoforms family C Brenner et al 884 intermembrane space (Pfaff and Klingenberg, 1968; proteins that coordinate mitochondrial outer membrane Pfaff et al., 1969). Therefore, this nucleotide-dependent permeabilization via still debated molecular mechanisms function implies a central role in energetic metabolism (for review, see Chipuk and Green, 2008). More and energetic compartmentation via the coupling of recently, a third major breakthrough has been made mitochondrial ATP synthesis to cytosolic delivery. in terms of role of ANT in apoptosis. Thus, ANT is Then, ANT antiport function is critical for many cell expressed as four tissue-specific isoforms, ANT1 to processes, notably in tumor cells, which have increased ANT4, and we and others postulated that each ANT metabolic requirements for DNA and protein synthesis isoform might have a specific role in influencing cell fate, (Gottlieb and Tomlinson, 2005). notably in cancer cells (Bauer et al., 1999; Zamora et al., In 1996, the discovery that ANT also functions as a 2004a; Le Bras et al., 2006; Gallerne et al., 2010). In this non-specific pore upon stimulation by ions and a variety review, we recapitulate our knowledge of the role that of molecules, such as calcium (Ca2 þ ) and ROS, as the various isoforms of ANT play in apoptosis, examine shown by reconstitution of native purified ANT into the expression and the function of the four ANT liposomes, constituted the first important breakthrough isoforms in cancer cells and discuss recent evidence to (Brustovetsky and Klingenberg, 1996; Ru¨ck et al., propose a novel classification of ANT isoforms and 1998). Later, a second breakthrough highlighted the their function in cancer cell death. critical involvement of ANT in the execution of the mitochondrial apoptosis pathway in various pathophy- siological and experimental models, such as ischemia– reperfusion, intoxication and chemotherapy (Marzo ANT: a bi-functional protein et al., 1998a; Cao et al., 2001; Haouzi et al., 2002; Malorni et al., 2009). For instance, ANT could influence ANT, as many proteins involved in cell death signaling, cell death through cooperation with pro-apoptotic harbors two (opposite) functions, both of which are proteins such as Bax, viral proteins (for example viral intricately involved in the control and regulation of protein R (Vpr) from HIV-1, PB1-F2 from Influenza) or cell fate (Halestrap and Brenner, 2003; Kroemer, et al., through participation in a mitochondrial polyprotein 2007). complex, the so-called permeability transition pore complex (PTPC) in diverse model systems such as A vital ADP/ATP translocase function human carcinoma cell lines, cardiomyocytes and neu- ANT constitutes the major protein in the mitochondrial rons (Crompton, 1999; Cao et al., 2001; De Giorgi et al., IM, in which it represents around 10% of the proteins. 2002; Brenner and Grimm, 2006) (Figure 1). However, It catalyzes the energetic process of ATP export from while experimental evidence clearly established a role of the mitochondrial matrix to the intermembrane space, ANT in the so-called MMP in some models of cancer, and conversely, the import of ADP from the intermem- other studies also showed that MMP could be ANT brane space to the matrix (Pfaff and Klingenberg, 1968; independent, but controlled by the Bcl-2 family Pfaff et al., 1969). The transport is electrogenic of proteins (Antonsson et al., 1997; Eskes et al., 1998). and drives the stoichiometric exchange of ATP4À and Bcl-2 family is composed of pro- and anti-apoptotic ADP3À. The enzymatic function of ANT has been Permeability transition Glycolysis 2+ G6P Ca ROS -induced uncoupling HK Pyruvate VDAC VDAC ROS ROS ANT U ANT UCP CypD OM 2+ OM IM Ca H+ H+ Pyruvate Fumarate Succinate TCA - + NAD+ H 0 H+ ATP - + m 1/2 O 2 ADP NADH 2 ADP - + II I III IV V ANT Ub e- ROS Cytc H+ H+ H+ ATP ROS Oxydative phosphorylation Figure 1 Scheme of mitochondrial functions involving the ANT. ANT possess diverse functions including the electrogenic exchange ADP/ATP across the IM, the participation to the PTPC stimulate by Ca2 þ and ROS, a mild uncoupling activity that is stimulated by anion superoxide, fatty acids and peroxydated lipids. All functions are modulated by the transmembrane inner potential, DCm, which is, at least in part, generated by the oxidative phosphorylation and the function of the respiratory complexes I to V. Cytc, cytochrome c; G6P, glucose-6-phosphate HK, hexokinase, TCA, tricarboxylic
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