Résumés
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.
Parties annexes
Références
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