ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 257, No. 1, August 15, pp. 154-169,1987 On the Origin of the Limited Control of Mitochondrial Respiration by the Adenine Nucleotide Translocator HANS V. WESTERHOFF, *,I PETER J. A. M. PLOMP, ALBERT K. GROEN, RONALD J. A. WANDERS, JAN A. BODE, AND KAREL VAN DAM Laboratory of Biochemistry, B. C. P. Jansen Institute, University of Amsterdam, P.O. Box 20151, 1000 HD Amsterdam, The Netherlands, and *Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Building 2, Room 319, Bethesda, Maryland 20892 Received January 12.198’7, and in revised form May 1,1987 A thermodynamic control theory previously developed has been applied to mitochon- drial oxidative phosphorylation with emphasis on the role of A,& and coupling and within the paradigm of delocalized chemiosmotic coupling. The basis for the observed distribution of flux control over the participating enzymes is shown to lie in the relative magnitudes of so-called ALn elasticity coefficients, i.e., the AfiH dependencies of the different mitochondrial processes. In particular the relatively strong Abn dependence of mitochondrial respiration is responsible for the significant role of the adenine nu- cleotide translocator in the control of oxidative phosphorylation. Uncoupling decreases the control exerted by this translocator on respiration but increases that exerted on phosporylation. 0 1987 Academic Press. Inc. Various authors [e.g., (l-7); for a review tons across the inner mitochondrial mem- see (S)] applied the theory of metabolic brane (A,ii,) is an important energetic in- control of Kacser and Burns (9) and Hein- termediate in oxidative phosphorylation rich and Rapoport (10) to the question of [(ll); for review, see (12,13)]. Surprisingly to what extent the adenine nucleotide little has however been said about the pos- translocator controls oxidative phosphor- sible control functions the proton trans- ylation. Thus they could quantitatively in- location steps may have with respect to ox- terpret the results obtained with titrations idative phosphorylation. Also in view of the of oxidative phosphorylation with car- suggestion (13, 14) that processes such as boxyatractyloside. They found that the flux uncoupling may have relevance in optimiz- control exerted by the adenine nucleotide ing oxidative phosphorylation, it would translocator on mitochondrial respiration seem important to consider the control is neither complete nor zero and, most in- properties of the proton translocating re- terestingly, is condition dependent. actions. In their experiments Groen et al. (2) and Gellerich et al. (3) examined the effect of a change in the (extramitochondrial) load on the system on the control of the adenine nucleotide translocator on oxidative phos- phorylation. In this paper we will focus on the role of AbH therein. It is now widely accepted that the elec- trochemical potential difference for pro- 1 To whom correspondence should be addressed. In (15) we have adapted and extended an already existing theory for rate control in metabolism to discussing metabolic control in thermodynamic terms. In this paper we illustrate the usefulness of the extended theory by applying it to the analysis of the control of oxidative phosphorylation by the adenine nucleotide translocator. For sim- plicity, we remain within the framework of the chemiosmotic coupling hypothesis. It is shown how the flux control coefficient 0003-9861/87 $3.00 Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any form reserved. 154