Factors determining the relative contribution of the adenine‐nucleotide translocator and the ADP‐regenerating system to the control of oxidative phosphorylation in isolated rat‐liver mitochondria

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Abstract
The control exerted by the adenine nucleotide translocator and the ADP-regenerating system on oxidative phosphorylation was studied in isolated rat-liver mitochondria respiring with succinate. 1 At intermediate rates of respiration the flux control coefficient (control strength) of the adenine nucleotide translocator on respiration was much higher with creatine/creatine kinase than with glucose/hexokinase as the ADP-regenerating system. In contrast, at the same rate of respiration the flux control coefficient of creatine kinase was much lower than that of hexokinase. 2 On addition of a small amount of carboxyatractyloside to mitochondria respiring in the presence of glucose/hexokinase or creatine/creatine kinase, the rate of respiration decreased abruptly and then increased again to a new steady state which was lower with creatine/creatine kinase than with glucose/hexokinase. In the new steady state, the extramitochondrial ATP/ADP ratio was lower with glucose/hexokinase than with creatine/creatine kinase. 3 At the same rate of respiration, the elasticity coefficient of creatine kinase towards the extramitochondrial ATP/ADP ratio was much higher than that of hexokinase. 4 The connectivity theorem [Kacser, H. and Burns, J. A. (1973) in Rate Control of Biological Processes (Davies, D. D., ed.) pp. 65–104, Cambridge University Press, London] which relates the flux control coefficients of two adjacent enzymes to their elasticity coefficients towards the common intermediate, provides an explanation for the difference in flux control coefficient of the adenine nucleotide translocator with the two ADP-regenerating systems. 5 Using principles developed by R. Heinrich and T. A. Rapoport [BioSystems 7, 130–136 (1975)], the flux control coefficients of the adenine nucleotide translocator and hexokinase on phosphorylation were also calculated from the elasticity coefficients of these enzymes towards the extramitochondrial ATP/ADP ratio and the controls exerted by these enzymes on the extramitochondrial ATP/ADP ratio. The calculated values were approximately 30% lower than the values measured directly. 6 The elasticity coefficient of the adenine nucleotide translocator towards the extramitochondrial ATP/ADP ratio was determined, using either the connectivity theorem of Kacser and Burns (loe. cit.) or a new connectivity theorem developed by Westerhoff (following paper in this journal). Good agreement was obtained using the different methods of calculation. 7 It is concluded that flux through the adenine nucleotide translocator, although in principle dependent on ([ATP]/[ADP])out, ([ATP]/[ADP])in and ΔΨ, is regulated primarily by ([ATP]/[ADP])out under the conditions used in this study.

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