Abstracts
Résumé
La translocase des nucléotides adényliques (ANT) réalise l’échange ATP/ADP entre le cytoplasme et la mitochondrie. Les isoformes ANT1 (musculaire) et ANT3 (ubiquitaire) exportent l’ATP produit par les phosphorylations oxydatives mitochondriales. L’isoforme ANT2 est spécifiquement exprimée dans les cellules en prolifération, dotées d’un métabolisme majoritairement glycolytique. ANT2 est ainsi associée à la dédifférenciation cellulaire, caractéristique majeure de la cancérogenèse. Son rôle serait d’importer dans la mitochondrie l’ATP produit par la glycolyse, énergie indispensable à différentes fonctions intramitochondriales, notamment au maintien du gradient de potentiel membranaire qui conditionne la survie et la prolifération cellulaires. Le mécanisme de régénération de ce gradient pourrait impliquer trois protéines majeures : l’hexokinase II, l’ANT2 et la partie F1 de l’ATP synthétase mitochondriale. Ainsi, l’ANT2, grâce à son rôle déterminant dans la croissance de la cellule tumorale, pourrait être choisie comme cible dans une stratégie anticancéreuse.
Summary
In the mitochondrial internal membrane, the adenine nucleotide translocator (ANT) carries out the ATP/ADP exchange between cytoplasm and mitochondrial matrix. Three isoforms with different kinetic properties are encoded from three different genes in Human : the muscle specific ANT1 and the ubiquitary ANT3 isoforms export ATP produced by mitochondrial oxidative phosphorylation (OXPHOS). The ANT2 isoform is specifically expressed in proliferative cells with a predominant glycolytic metabolism and is associated with cellular undifferentiation which is a major characteristic in carcinogenesis. Its role would be to import into mitochondria ATP produced by the glycolysis, energy essential to several intramitochondrial functions, particularly to maintenance of the membrne potential (ΔΨm), conditioning cellular survival and proliferation. The mechanism of regeneration of this ΔΨm gradient would involve at least three major proteins : the hexokinase II isoform, the ANT2 isoform and the F1 part of the mitochondrial ATP synthase complex. Taking into account this major role of ANT2 in cell proliferation and the very low expression of this isoform in differentiated tissues, this protein or its transcript could be chosen as a target for an anticancer strategy. Furthermore, previous studies showed that molecules of the cisplatin family, used as chemotherapeutic agents, led to the destruction of the mitochondrial membrane potential and thus to cell death. Does the anticancer effect of these molecules result, at least partially, from this mitochondrial aggression ? If it is the case, the ANT2 isoform, mainly involved in the generation of this potential by its ATP4–/ADP3– exchange, could be considered as a more specific targeting by an RNA interference approach.
Appendices
Références
- 1. Capaldi RA, Halphen DG, Zhang YZ, Yanamura W. Complexity and tissue specificity of the mitochondrial respiratory chain. J Bioenerg Biomembr 1988 ; 20 : 291-311.
- 2. Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, et al. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 2003 ; 426 : 39-44.
- 3. Stepien G, Torroni A, Chung A, et al. Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during cell differentiation. J Biol Chem 1992 ; 267 : 14592-7.
- 4. Li K, Hodge JA, Wallace DC. OXBOX, a positive transcriptional element of the heart-skeletal muscle ADP/ATP translocator gene. J Biol Chem 1990 ; 265 : 20585-8.
- 5. Giraud S, Bonod-Bidaud C, Wesolowski-Louvel M, Stepien G. Expression of human ANT2 gene in highly proliferative cells : GRBOX, a new transcriptional element, is involved in the regulation of glycolytic ATP import into mitochondria. J Mol Biol 1998 ; 281 : 409-18.
- 6. Luciakova K, Barath P, Poliakova D, et al. Repression of the human adenine nucleotide translocase-2 gene in growth-arrested human diploid cells : the role of nuclear factor-1. J Biol Chem 2003 ; 278 : 30624-33.
- 7. Ku DH, Kagan J, Chen ST, et al. The human fibroblast adenine nucleotide translocator gene : molecular cloning and sequence. J Biol Chem 1990 ; 265 : 16060-3.
- 8. Barath P, Luciakova K, Hodny Z, et al. The growth-dependent expression of the adenine nucleotide translocase-2 (ANT2) gene is regulated at the level of transcription and is a marker of cell proliferation. Exp Cell Res 1999 ; 248 : 583-8.
- 9. Jang JY, Lee CE. Mitochondrial adenine nucleotide translocator 3 is regulated by IL-4 and IFN-gamma via STAT-dependent pathways. Cell Immunol 2003 ; 226 : 11-9.
- 10. Amiri H, Karlberg O, Andersson SE. Deep origin of plastid/parasite ATP/ADP translocases. J Mol Evol 2003 ; 56 : 137-50.
- 11. Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells : identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 2001 ; 276 : 43407-12.
- 12. Pedersen PL, Mathupala S, Rempel A, et al. Mitochondrial bound type II hexokinase : a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 2002 ; 1555 : 14-20.
- 13. Napoli L, Bordoni A, Zeviani M, et al. A novel missense adenine nucleotide translocator-1 gene mutation in a Greek adPEO family. Neurology 2001 ; 57 : 2295-8.
- 14. Siciliano G, Tessa A, Petrini S, et al. Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. Neuromuscul Disord 2003 ; 13 : 162-5.
- 15. Jordens EZ, Palmieri L, Huizing M, et al. Adenine nucleotide translocator 1 deficiency associated with Sengers syndrome. Ann Neurol 2002 ; 52 : 95-9.
- 16. Graham BH, Waymire KG, Cottrell B, et al. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat Genet 1997 ; 16 : 226-34.
- 17. Faustin B, Rossignol R, Rocher C, et al. Mobilization of adenine nucleotide translocators as molecular bases of the biochemical threshold effect observed in mitochondrial diseases. J Biol Chem 2004 ; 279 : 20411-21.
- 18. Kokoszka JE, Waymire KG, Levy SE, et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 2004 ; 427 : 461-5.
- 19. Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today 1997 ; 18 : 44-51.
- 20. Brenner C, Cadiou H, Vieira HL, et al. Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene 2000 ; 19 : 329-36.
- 21. Bauer MK, Schubert A, Rocks O, Grimm S. Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J Cell Biol 1999 ; 147 : 1493-502.
- 22. Zamora M, Granell M, Mampel T, Vinas O. Adenine nucleotide translocase 3 (ANT3) overexpression induces apoptosis in cultured cells. FEBS Lett 2004 ; 563 : 155-160.
- 23. Ara G, Kusumoto T, Korbut TT, et al.Cis-diamminedichloroplatinum(II) resistant human tumor cell lines are collaterally sensitive to PtCl4(Rh-123)2 : evidence for mitochondrial involvement. Cancer Res 1994 ; 54 : 1497-502.
- 24. Harper ME, Antoniou A, Villalobos-Menuey E, et al. Characterization of a novel metabolic strategy used by drug-resistant tumor cells. Faseb J 2002 ; 16 : 1550-7.
- 25. Ludwig B, Bender E, Arnold S, et al. Cytochrome C oxidase and the regulation of oxidative phosphorylation. Chem Biochem 2001 ; 2 : 392-403.
- 26. Chevrollier A, Loiseau D, Gautier F, et al. ANT2 expression under hypoxic conditions produces opposite cell-cycle behavior in 143B and HepG2 cancer cells. Mol Carcinogen 2005 ; 42 : 1-8.