Mobilization of Adenine Nucleotide Translocators as Molecular Bases of the Biochemical Threshold Effect Observed in Mitochondrial Diseases

Abstract

The existence of a biochemical threshold effect in the metabolic expression of oxidative phosphorylation deficiencies has considerable implications for the understanding of mitochondrial bioenergetics and the study of mitochondrial diseases. However, the molecular bases of this phenomenon remain unclear. We report here a new mechanism to explain this threshold effect, based on a reserve of enzymes not initially participating in the respiratory rate that can be activated either to respond to a flux increase or to compensate for a defect induced by a mutation. We show that this mobilization occurs through 1) the assembly of inactive adenine nucleotide translocator isoform 1 subunits into oligomeric active carriers or 2) conformational changes in the adenine nucleotide translocator isoform 1 in a permeability transition pore-like structure. We discuss how these transitions are sensitive to the steady state of oxidative phosphorylation functioning or tissue and analyze their consequences on the threshold effect.

The proximal N-terminal amino acid residues are required for the coupling activity of the bovine heart mitochondrial factor B

“…The cosedimentation of the ADP/ATP carrier with FoF 1 -ATPase is consistent with the recently characterized form of the rat liver mitochondrial enzyme, the ATP synthasome [26,27]. Mass spectrometry analysis of the peptides derived from trypsin digestion of the 31 kDa band excised from lanes 4 and 6 of panel A, identified this band as isoform 1 of the ADP/ATP carrier (data not shown), which is a major isoform expressed in the heart and skeletal muscles [28]. Recombinant factor B (panel B) was mostly found in fraction 2 (a band with M r~2 2 kDa), in agreement with a previous report that at high protein concentrations, factor B forms oligomers, presumably trimers [14].…”

The permeability transition pore complex in cancer cell death

“…Notably, the respective contribution of ANT and CypD to the PTP has recently been questioned in several studies conducted in mice that have been engineered to deplete these proteins (Kokoszka et al, 2004;Baines et al, 2005;Nakagawa et al, 2005) (see below). Adenine nucleotide translocase, a major candidate for the IM pore, has been isolated in several protein subcomplexes composed of various ratios of VDAC and CypD (for a review, see Crompton et al, 2002;Faustin et al, 2004), as well as in a complex with the F0F1-ATPase and the phosphate carrier (Ko et al, 2003). The state of protein oligomerization might depend on the respiratory rate of mitochondria (Faustin et al, 2004), rendering the isolation of a unique complex a challenge.…”

“…Adenine nucleotide translocase, a major candidate for the IM pore, has been isolated in several protein subcomplexes composed of various ratios of VDAC and CypD (for a review, see Crompton et al, 2002;Faustin et al, 2004), as well as in a complex with the F0F1-ATPase and the phosphate carrier (Ko et al, 2003). The state of protein oligomerization might depend on the respiratory rate of mitochondria (Faustin et al, 2004), rendering the isolation of a unique complex a challenge. However, a consensus emerged to consider the PTP as a multiprotein complex of about 600 kDa (Beutner et al, 1996a;Faustin et al, 2004).…”

“…The state of protein oligomerization might depend on the respiratory rate of mitochondria (Faustin et al, 2004), rendering the isolation of a unique complex a challenge. However, a consensus emerged to consider the PTP as a multiprotein complex of about 600 kDa (Beutner et al, 1996a;Faustin et al, 2004). Its components could be involved in several subcomplexes, dedicated to the maintenance of the energetic metabolism and/or to the execution of cell death (Crompton et al, 2002;Zoratti et al, 2005).…”

Quel rôle spécifique pour ANT2 dans une cellule cancéreuse ?

“…L'implication de l'ANT1 dans divers syndromes a été confirmée chez la souris par une invalidation du gène ANT1 [16]; ces animaux présentent toutes les caractéristiques physiologiques, histologiques et biochimiques des myopathies et des cardiomyopathies: une déficience de l'état 3 de la respiration, des fibres rouges déchiquetées, une hypertrophie cardiaque, une élévation des taux d'acides lactique et citrique et, enfin, une intolérance à l'exercice. Par ailleurs, de récentes études ont montré que cette isoforme ANT1 aurait un rôle dans l'effet seuil (threshold effect) observé dans les maladies mitochondriales [17]. En revanche, aucune étude ne fait référence à l'existence de maladies liées à une mutation de l'isoforme « glycolytique » ANT2 ou de l'iso- forme ubiquitaire ANT3.…”