Adenine nucleotide translocator

In both intermediate and maximum rates of respiration, control is distributed between several different steps, including the activity of the adenine nucleotide translocator (Groen et al., 1983). It is now recognized that the idea of a simple rate-limiting step for a metabolic pathway is simplistic and that control is shared by all steps although to different extents (Kacserand Bums, 1978 Fell, 1992). Each step in a pathway has a flux control coefficient (FCC) defined as ... 

Calcium oxalate monohydrate responsible for the formation of most kidney stones significantly increased mitochondrial superoxide production in renal epithelial cells [42], Recombinant human interleukin IL-(3 induced oxygen radical generation in alveolar epithelial cells, which was suppressed by mitochondrial inhibitors 4 -hydroxy-3 -methoxyacetophe-none and diphenylene iodonium [43]. Espositio et al. [44] found that mitochondrial oxygen radical formation depended on the expression of adenine nucleotide translocator Anti. Correspondingly, mitochondria from skeletal muscle, heart, and brain from the Antl-deficient mice sharply increased the production of hydrogen peroxide. 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

Cardiolipin forms also tight complexes, with the adenine nucleotide translocator (ATM) affecting its translocator activity (Beyer and Nuscher, 1996). Six cardiohpin residues are tightly bound to lysines (Beyer and Klingenberg, 1985). Removal of these lipids renders the translocator inactive, but activity can be reconstituted by adding cardiolipin. It has also a pivotal role as a boundary hpid of various proteins such as NADH ubiquinone oxireductase (Hoch, 1992) or cytochrome c oxidase (Ushmorov et al, 1999 Vik et al, 1981). 

Vieira, H.L.A., Haouzi, D., Hamel, C.E., Jacotot, E., Belzacq, A.S., Bienner, C., and Kroemer, G., 2000, PermeabUization ofthe mitochrondrial inner membrane during apoptosis impact ofthe adenine nucleotide translocator. Cell Death and Differentiation 1 1146-1154. 

Heldt, H. W. 1969. Adenine nucleotide translocation in spinach chloroplasts. FEBS Lett. 5, 11-14. 

Ciapaite, J., Van Eikenhorst, G., Bakker, S.J.L., Diamant, M., Heine, R.J., Wagner, M.J., Westerhofif, H.V. and Krab, K. (2005) Modular kinetic analysis of the adenine nucleotide translocator-mediated effects of palmitoyl-CoA on the oxidative phosphorylation in isolated rat liver mitochondria. Diabetes 54, 944-951. 

The mitochondrial translocators which have been most carefully assessed with respect to their role in control of metabolism are (1) the adenine nucleotide translocator with respect to its role in the control of respiration (2) the liver pyruvate transporter and the control of gluconeogenesis and (3) kidney glutamate and glutamine transport and their control of ammoniagenesis. 

The mechanism of control of mitochondrial respiration remains an important question of mitochondrial bioenergetics. It was initially proposed by Chance and Williams [220] that respiration is kinetically controlled by ADP availability, an hypothesis which has received renewed support by the studies of Jacobus et al. [221]. However, the major controversy has centered on whether or not the adenine nucleotide translocator is rate limiting, or even rate controlling, for respiration. As a consequence of this controversy, two hypotheses have emerged over the past several years, one of which has been recently modified. Wilson and Ericinska [222] have proposed a near-equilibrium hypothesis , whereas others have advocated variations of a translocase hypothesis in which the adenine nucleotide translocator is either rate limiting or rate controlling for respiration. 

At the present time, it is the opinion of the present reviewers that Wilson and collaborators have not provided sufficient evidence to conclude that the adenine nucleotide carrier is electroneutral and near equilibrium, nor have they conclusively shown that the first two sites of oxidative phosphorylation are in near equilibrium, especially in view of the likelihood that the P/O ratio of the first two sites is 1.5 rather than 2 [230,231]. Therefore, we conclude that their studies do not convincingly exclude a role for the adenine nucleotide translocator in the control of mitochondrial respiration. 

Additional studies [212,218,219,242,243] to quantitate the role of the adenine nucleotide translocator in the control of mitochondrial respiration have been performed utilizing inhibitor titrations with carboxyatractyloside. The results indicated that in State 4 (no ADP), no control was exerted by the translocator. However, as the rate of respiration was increased up to State 3 (excess ADP), the control strength of the carrier increased to a maximum value of 30%, at 80% of State 3 respiration. These studies indicate that the adenine nucleotide translocator cannot be considered to be the only rate-controlling step in oxidative phosphorylation. However, they do provide experimental support for a controlling role for the carrier at intermediate to maximal levels of respiration. An important corollary of these studies is that the reaction rate may be altered by a change in substrate concentration (elasticity). It is also clear that to confirm these studies quantitatively, they must be extended to intact cells. Although such studies have been more difficult, the results are compatible with the conclusion reached by Tager et al. [212]. 

From these studies and those of Tager, an intermediate view is emerging with respect to the role of the adenine nucleotide translocator in the control of mitochondrial respiration. This view suggests that a variable degree of control is exerted depending upon the metabolic state, substrate availability, etc., such that control may be considerable or minimal. Such a view also implies that the control strength may vary from tissue to tissue and from cell to cell within the tissue. 

At the present time, it is not possible to resolve the controversies that exist with regard to factors controlling the rate of respiration. However, it is our view that the available data do not provide any support for the extreme views. It seems likely that the adenine nucleotide translocator is not the sole controlling or rate-limiting step for respiration. Nor does it appear likely that it has no role. The degree of control exerted is a variable, but important factor. 

The essential role of cytochrome c release from injured mitochondria in the activation of caspase 9 has been alluded to above. This pathway is especially important in proapoptotic stimuli that are not initiated by surface receptors for apoptosis, such as UV irradiation, and may involve mitochondrial dependent pathways [83]. Continued respiration in the presence of an open mitochondrial pore may result in the generation of reactive oxygen species. Release of cytochrome c may be mediated by the opening of the mitochondrial FT pore, a non-selective channel whose composition is only partially defined [84]. Inhibitors of FT pore opening, such as cyclosporine, which binds to the adenine nucleotide translocator (ANT), a component of the FT pore, and bongkrekic acid, as well as Bcl-2, prevent cytochrome c release and inhibit apoptosis [85] whereas activators of the FT pore, such as atractyloside and Bax induce it [86]. Oxidants can rupture the outer membrane of mitochondria and release caspase-activating proteins [87]. Some studies have shown cytochrome c release before collapse of the mitochondrial membrane potential [83] suggesting alternate control of the FT pore. Many, but not all, of the members of the Bd-2 family of proteins reside in the inner mitochondrial membrane, form ionic channels in hpid membranes and increase rates of proton extrusion in mitochondria [88] and thus may control the FT pore. The antiapoptotic and mitochondrial affects of Bd-2 are independent of caspase activity as they occur in the presence of caspase inhibitors and also in yeast that lack caspases [86]. 

ACE angiotensin converting enzyme ANT adenine nucleotide translocator... 

Streicher-Scott J, Lapidus R, SokolovePM. Thereconstimtedmitochondrial adenine nucleotide translocator effects of lipid polymorphism. Arch Biochem Biophy 1994 315 548-554. 

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