The Signal Transduction Function for Oxidative Phosphorylation Is at Least Second Order in ADP*

To maintain ATP constant in the cell, mitochondria must sense cellular ATP utilization and transduce this demand to F0-F1-ATPase. In spite of a considerable research effort over the past three decades, no combination of signal(s) and kinetic function has emerged with the power to explain ATP homeostasis in all mammalian cells. We studied this signal transduction problem in intact human muscle using 31P NMR spectroscopy. We find that the apparent kinetic order of the transduction function of the signal cytosolic ADP concentration ([ADP]) is at least second order and not first order as has been assumed. We show that amplified mitochondrial sensitivity to cytosolic [ADP] harmonizes with in vitro kinetics of [ADP] stimulation of respiration and explains ATP homeostasis also in mouse liver and canine heart. This result may well be generalizable to all mammalian cells.

[1]  A. Lehninger,et al.  The affinity of mitochondrial oxidative phosphorylation mechanisms for phosphate and adenosine diphosphate. , 1967, Proceedings of the National Academy of Sciences of the United States of America.

[2]  V. Trézéguet,et al.  Chemical, immunological, enzymatic, and genetic approaches to studying the arrangement of the peptide chain of the ADP/ATP carrier in the mitochondrial membrane , 1993, Journal of bioenergetics and biomembranes.

[3]  William,et al.  Mitochondrial respiratory control. Evidence against the regulation of respiration by extramitochondrial phosphorylation potentials or by [ATP]/[ADP] ratios. , 1982, The Journal of biological chemistry.

[4]  A. Koretsky,et al.  Insights into cellular energy metabolism from transgenic mice. , 1995, Physiological reviews.

[5]  G. Brandolin,et al.  Kinetics of Pi-Pi exchange in rat liver mitochondria. Rapid filtration experiments in the millisecond time range. , 1985, Biochemistry.

[6]  J. Rosing,et al.  Comparison of ADP and ATP as substrates for the adenine nucleotide translocator in rat-liver mitochondria. , 1973, Biochimica et biophysica acta.

[7]  Y. Shinohara,et al.  Translocation of Loops Regulates Transport Activity of Mitochondrial ADP/ATP Carrier Deduced from Formation of a Specific Intermolecular Disulfide Bridge Catalyzed by Copper-o-Phenanthroline (*) , 1995, The Journal of Biological Chemistry.

[8]  H. Gutfreund,et al.  Enzyme kinetics , 1975, Nature.

[9]  M. Kushmerick,et al.  Separate measures of ATP utilization and recovery in human skeletal muscle. , 1993, The Journal of physiology.

[10]  D. Koshland,et al.  Amplification and adaptation in regulatory and sensory systems. , 1982, Science.

[11]  G. Dudley,et al.  Influence of mitochondrial content on the sensitivity of respiratory control. , 1987, The Journal of biological chemistry.

[12]  B CHANCE,et al.  Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. , 1955, The Journal of biological chemistry.

[13]  K. Lanoue,et al.  Studies of Physiological Control of ATP Synthesis , 1995 .

[14]  C. Duyckaerts,et al.  Kinetic mechanism of the exchanges catalysed by the adenine-nucleotide carrier. , 2005, European journal of biochemistry.

[15]  W. Nyhan.  Asbjörn Fölling and phenylketonuria , 1984 .

[16]  K F LaNoue,et al.  Rates of various reactions catalyzed by ATP synthase as related to the mechanism of ATP synthesis. , 1991, The Journal of biological chemistry.

[17]  H. Rottenberg,et al.  THE THERMODYNAMIC DESCRIPTION OF ENZYME-CATALYZED REACTIONS , 1973 .

[18]  R S Balaban,et al.  Relation between work and phosphate metabolite in the in vivo paced mammalian heart. , 1986, Science.

[19]  H. Westerhoff,et al.  Quasi-linear relationship between Gibbs free energy of ATP hydrolysis and power output in human forearm muscle. , 1995, The American journal of physiology.

[20]  M. Hochberg,et al.  Control engineering , 1991, Nature.

[21]  E. C. Slater,et al.  The value of ΔG° for the hydrolysis of ATP☆ , 1972 .

[22]  G. Radda,et al.  Kinetic control of mitochondrial ATP synthesis. , 1986, Biochemistry.

[23]  H. Westerhoff,et al.  Thermodynamics and Control of Biological Free-Energy Transduction , 1987 .

[24]  F. Palmieri,et al.  Functional properties of purified and reconstituted mitochondrial metabolite carriers , 1993, Journal of bioenergetics and biomembranes.

[25]  B. Chance.  Reaction of Oxygen with the Respiratory Chain in Cells and Tissues , 1965, The Journal of general physiology.

[26]  E. Feigl,et al.  Adrenergic Coronary Vasoconstriction Helps Maintain Uniform Transmural Blood Flow Distribution During Exercise , 1988, Circulation research.

[27]  S Nioka,et al.  Control of oxidative metabolism and oxygen delivery in human skeletal muscle: a steady-state analysis of the work/energy cost transfer function. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Haas,et al.  Stimulation of K-C1 cotransport in rat red cells by a hemolytic anemia-producing metabolite of dapsone. , 1989, The American journal of physiology.

[29]  Boris N. Kholodenko,et al.  Biothermokinetics of the living cell , 1996 .

[30]  H. Heldt,et al.  Adenine nucleotide translocation of mitochondria. Kinetics of the adenine nucleotide exchange. , 1969, European journal of biochemistry.