Abstract
Some historical aspects of development of the concepts of functional coupling, metabolic channelling, compartmentation and energy transfer networks are reviewed. Different quantitative approaches, including kinetic and mathematical modeling of energy metabolism, intracellular energy transfer and metabolic regulation of energy production and fluxes in the cells in vivo are analyzed. As an example of the system with metabolic channelling, thermodynamic aspects of the functioning the mitochondrial creatine kinase functionally coupled to the oxidative phosphorylation are considered. The internal thermodynamics of the mitochondrial creatine kinase reaction is similar to that for other isoenzymes of creatine kinase, and the oxidative phosphorylation process specifically influences steps of association and dissociation of MgATP with the enzyme due to channelling of ATP from adenine nucleotide translocase. A new paradigm of muscle bioenergetics - the paradigm of energy transfer and feedback signaling networks based on analysis of compartmentation phenomena and structural and functional interactions in the cell is described. Analysis of the results of mathematical modeling of the compartmentalized energy transfer leads to conclusion that both calcium and ADP, which concentration changes synchronously in contraction cycle, may simultaneously activate oxidative phosphorylation in the muscle cells in vivo. The importance of the phosphocreatine circuit among other pathways of intracellular energy transfer network is discussed on the basis of the recent data published in the literature, with some experimental demonstration. The results of studies of perfused rat hearts with completely inhibited creatine kinase show significantly decreased work capacity and respectively, energy fluxes, in these hearts in spite of significant activation of adenylate kinase system (Dzeja et al. this volume). These results, combined with those of mathematical analysis of the energy metabolism of hearts of transgenic mice with switched off creatine kinase isoenzymes confirm the importance of phosphocreatine pathway for energy transfer for cell function and energetics in mature heart and many other types of cells, as one of major parts of intracellular energy transfer network and metabolic regulation.
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References
Nagle S: Regelprobleme im Energiestoffwechel des Herzmuskels. Klin Wsch 48: 1075–1089, 1970
Meyer RA, Sweeney HL, Kushmerick MJ: A simple analysis of the ‘phosphocreatine shuttle’. Am J Physiol 246: C365–C377, 1984
Saks VA, Khuchua ZA, Vasilyeva EV, Belikova Yu O, Kuzuetsov AV: Metabolic compartmentation and substrate channelling in muscle cells. Role of coupled creatine kinases in in vivo regulation of cellular respiration–a synthesis. Mol Cell Biochem 133/134: 155–192, 1994
Sjostrand FS: The structure of mitochondrial membranes: A new concept. J Ultrastruct Res 64: 217–245, 1978
Klingenberg M: Muskelmitochondrien. In: K Kramer, O Krayer, E Lehnartz, A v Muralt, HH Weber (eds). Ergebnisse der Physiologic. Biologischen Chemie und Experimentellen Pharmakologie. Springer-Verlag, Berlin, 1964, pp 132–189
Morrison JF, Cleland WW: Isotope exchange studies of the mechanism of the reaction catalyzed by adenosine triphosphate: Creatine phosphotransferase. J Biol Chem 241: 637–683, 1966
Saks VA, Chernousova GB, Gukovsky DE, Smirnov VN, Chazov EI: Studies of energy transport in heart cells. Mitochondrial isoenzyme of creatine kinase: Kinetic properties and regulatory action of Mg ions. Eur J Biochem 57: 273–290, 1975
van Dorsten FA, Furter R Bijkerk M, Wallimann T, Nicolay K: The in vitro kinetics of mitochondrial and cytosolic creatine kinase determined by saturation transfer 31P-NMR Biochim Biophys Acta 1274: 59–66, 1996
Sols A, Marco R: Concentrations of metabolites and binding sites. Implications in metabolic regulation. Curr Top Cell Reg 2: 227–273, 1970
Mitchell P: Compartmentation and communication in living systems. Ligand conduction: A general catalytic principle in chemical, osmotic and chemiosmotic reaction systems. Eur J Biochem 95: 1–20, 1979
Wiseman RW, Jeneson JAL, Kushmerick MJ: Why is the sensitivity of mitochondria to ADP over tenfold lower in permeabilized cells than in vivo? Biothermokinetics of the Living Cell. Biothermokinetics Press, Amsterdam, 1996, pp 124–127
Fritz-Wolf K, Schnyder T, Wallimann T, Kabsch W: Structure of mitochondrial creatine kinase. Nature 381: 341–345, 1996
Saks VA, Ventura-Clapier RJ: Biochemical organization of energy metabolism in muscle. J Biochem Org 1: 9–29, 1992
Jacobus WE, Saks VA: Creatine kinase of heart mitochondria: Changes in its kinetic properties induced by coupling to oxidative phosphorylation. Arch Biochem Biophys. 219: 167–178, 1982
Nageswara Rao BD, Cohn M: 31P-NMR of enzyme-bound substrates of rabbit muscle creatine kinase. Equilibrium constants, interconversion rates, and NMR parameters of enzyme-bound complexes. J Biol Chem 256: 1716–1721, 1981
Burbaum JJ, Knowles JR: Internal thermodynamics of enzymes Determined by equilibrium quench: Values of Kint for enolase and creatine kinase. Biochemistry 28: 9306–9317, 1989
Albery WJ, Knowles JR: Evolution of enzyme function and the development of catalytic efficiency. Biochemistry 15: 5631–5640, 1976
Burbaum JJ, Raines RT, Albery J, Knowles JR: Evolutionary optimization of the catalytic effectiveness of an enzyme. Biochemistry 28: 9293–9305, 1989
Lowson JWR, Veech RL: Effect of pH and free Mg2+ on the Keq of the creatine kinase reaction and other phosphate hydrolases and phosphate transfer reactions. J Biol Chem 254: 6528–6537, 1979
Aliev MK, Saks VA: Mathematical modelling of intracellular transport processes and the creatine kinase system: A probability approach. Mol Cell Biochem 133/134: 333–346, 1994
Aliev MK, Saks VA: Compartmentalized energy transfer in cardiomyocytes: Use of mathematical modelling for analysis of in vivo regulation of respiration. Biophys J 73: 428–445, 1997
Saks VA, Aliev MK: Is there the creatine kinase equilibrium in working heart cells? Biochem Biophys Res Comm 227: 360–367, 1996
Balaban RS, Kantor HL, Katz LA, Briggs RW: Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science 232: 1121–1123, 1986
Balaban RS, Heneman FW: Control of mitochondrial respiration in the heart in vivo. Mol Cell Biochem 89: 191–197, 1989
Katz LA, Swain JA, Portman MA, Balaban RS: Relation between phosphate metabolites and oxygen consumption of heart in vivo. Am J Physiol 256: H265–H274, 1989
Mootha VK, Arai AE, Balaban RS: Maximum oxidative phosphorylation capacity of the mammalian heart. Am J Physiol 272: H769–H775, 1997
Hochachka PW, Matheson GO: Regulating ATP turnover rates over broad dynamic work ranges in skeletal muscles. J Appl Physiol 73: 1697–1703, 1992
Hochachka PW, McClelland GB: Cellular metabolic homeostasis during large scale change in ATP turnover rates in muscles. J Exp Biol 200: 381–386, 1997
Chance B, Leigh JS, Kent J, McCully K, Nioka S, Clark BJ, Maris JM, Graham T: Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance. Proc Natl Acad Sci USA 83: 9458–9462, 1986
Ammann H, Noël J, Tejedor A, Boulanger Y, Gougoux A, Vinay P: Could cytoplasmic concentration gradients for sodium and ATP exist in intact renal cells? Can J Physiol Pharmacol 73: 421–435, 1995
Ovaldi J: Cell architecture and metabolic channelling. Springer Verlag, New York-Berlin-London-Paris, 1995, pp 1–250
Agius L, Sherratt HSA (eds).: Channelling in Intermediary Metabolism. Portland Press, London and Miami, 1997, pp 1–342
Bereiter-Hahn J, Voth M: Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion and fission of mitochondria. Micro Res Tech 27: 198–219, 1994
Rostovtseva T, Colombini M: VDAC channels mediate and gate the flow of ATP: Implications for the regulation of mitochondrial function. Biophys J 72: 1954–1962, 1997
Hodge T, Colombini M: Regulation of metabolic flux through voltagegating of VDAC channels. J Membr Biol 157: 271–279, 1997
Heiden M, Hilschmann N, Thinnes FP, Kroll K: Proteins of cytosol and amniotic fluid increase the voltage dependence of human type-1 porin. J Bioenerg Biomembr 28: 171–180, 1996
Reymann S, Flörke H, Heiden M, Jakob C, Stadtmuller U, Steinacker P, Lalk VE, Pardowitz I, Thinnes FP: Further evidence for multitopological localization of mammalian porin (VDAC) in the plasmalemma forming part of a chloride channel complex affected in cystic fibrosis and encephalomyopathy. Biochem Mol Medicine 54: 75–87, 1995
Beutner G, Ruck A, Riede B, Welte W, Brdiczka D: Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore. FEBS Lett 396: 189–195, 1996
Clark JF, Kuznetsov AV, Radda GK: ADP regenerating enzyme systems in mitochondria of guinea pig myometrium and heart. Am J Physiol 272: C399–C404, 1997
McCabe ERB: Microcompartmentation of energy metabolism at the outer mitochondrial membrane: Role in diabetes mellitus and other diseases. J Bioenerg Biomembr 26: 317–325, 1994
Laterveer FD, Nicolay K, Gellerich FN: ADP delivery from adenylate kinase in the mitochondrial intermembrane space to oxidative phosphorylation increases in the presence of macromolecules. FEBS Lett 386: 255–259, 1996
Brdiczka D, Wallimann T: The importance of outer mitochondrial compartment in regulation of energy metabolism. Mol Cell Biochem 133/134: 69–84, 1994
Kushmerick MJ, Podolsky RJ: Ion mobility in muscle cells. Science 166: 1297–1298, 1969
Nicolay K, van der Toorn, Dijkhuizen RM: In vivo diffusion spectroscopy. An overview. NMR Biomed 8: 365–374, 1995
Walter H, Brooks DE: Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation. FEBS Lett 361: 135–139, 1995
Oplatka A: The role of water in the mechanism of muscular contraction. FEBS Lett 355: 1–3, 1994
Weiss JN, Lamp ST: Glycolysis preferentially inhibits ATP-sensitive K+ channels in isolated guinea pig cardiac myocytes. Science 238: 67–69, 1987
Opie LH: Cardiac metabolism–emergence, decline and resurgence. Cardiovasc Res 26: 721–733, 1992
Kuzuetsov AV, Tiivel T, Sikk P, Kaambre T, Kay L, Daneshrad Z, Rossi A, Kadaja L, Peet N, Seppet EK, Saks VA: Striking differences between kinetics of regulation of respiration by ADP in slow-twitch and fasttwitch muscles in vivo. Eur J Biochem 241: 909–915, 1996
Veech RL, Lawson JWR, Cornell NW, Krebs HA: Cytosolic phosphorylation potential. J Biol Chem 254: 6538–6547, 1979
Kushmerick MJ: Skeletal muscle: A paradigm for testing principles of bioenergetics. J Bioenerg Biomembr 27: 555–569, 1995
Bessman SP, Geiger PJ: Transport of energy in muscle. The phosphorylcreatine shuttle. Science 211: 448–452, 1981
Gercken G, Schlette U: Metabolite status of the heart in acute insufficiency due to 1-fluoro-2,4-dinitrobenzene. Experientia 24: 17–18, 1968
Gudbjarnason S, Mathes P, Ravens KG: Functional compartmentation of ATP and creatine phosphate in heart muscle. J Mol Cell Cardiol 1: 325–339, 1970
Saks VA, Ventura-Clapier R (eds).: Cellular Bioenergetics: Role of Coupled Creatine Kinase. Kluwer Academic Publishers, 1994, pp 1–346
Williams DA: Mechanisms of calcium release and propagation in cardiac cells. Do studies with confocal microscopy add to our understanding? Cell Calcium 14: 724–735, 1993
Rizzuto R, Bastianutto C, Brini M, Murgia M, Pozzan T: Mitochondrial Ca2+ homeostasis in intact cells. J Cell Biol 126: 1183–1194, 1994
Cheng H, Lederer WJ, Cannell MB: Calcium sparks: Elementary events underlying excitation-contraction coupling in heart muscle. Science 262: 740–744, 1993
Cannell MB, Cheng H, Lederer WJ: The control of calcium release in heart muscle. Science 268: 1045–1049, 1995
Lipp P, Niggli E: Modulation of calcium release in cultured neonatal cardiac myocytes. Insight from subcellular release patterns revealed by confocal microscopy. Circ Res 74: 979–990, 1994
Tanaka H, Kawanishi T, Matsuda T, Takahashi M, Shigenobu K: Intracellular free calcium movements in cultured cardiac myocytes as shown by rapid scanning confocal microscopy. J Cardiovasc Pharmacol 27: 761–760, 1996
Minamikawa T, Cody SH, Williams DA: In situ visualization of spontaneous calcium waves within perfused whole rat heart by confocal imaging. Am J Physiol 272: H236–H243, 1997
Isenberg G, Etter EF, Wendt-Gallitelli MF, Schiefer A, Carrington WA, Tuft RA, Fay FS: Intrasarcomere [Ca2+] gradients in ventricular myocytes revealed by high speed digital imaging microscopy. Proc Natl Acad Sci USA 93: 5413–5418, 1996
Mironneau J, Amaudeau S, Macrez-Lepretre, Boittin FX: Ca2+ sparks and Ca2+ waves activate different Ca2+-dependent ion channels in single myocytes from rat portal vein. Cell Calcium 20: 153–160, 1996
Fiolet JWT, Baartscheer A, Schumacher CA: Intracellular [Ca2+] and Vo2 after manipulation of the free-energy of the Na+/Ca2+-exchanger in isolated rat ventricular myocytes. J Mol Cell Cardiol 27: 1513–1525, 1995
Janiak R, Lewartowsky B, Langer GA: Functional coupling between sarcoplasmic reticulum and Na/Ca exchange in single myocytes of guinea pig and rat heart. J Mol Cell Cardiol 28: 253–264, 1996
Carmeliet E: A fuzzy subsarcolemmal space for intracellular Na in cardiac cells? Cardiovasc Res 26: 433–442, 1992
Wallimann T: 31P-NMR-measured creatine kinase reaction flux in muscle: A caveat! J Musc Res Cell Motil 17: 177–181, 1996
Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM: Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281: 31–40, 1992
Wallimann TW, Hemmer W: Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem 133/134: 193–220, 1994
Wyss M, Smeitnik J, Wever RA, Wallimann T: Mitochondrial creatine kinase: A key enzyme of aerobic energy metabolism. Biochim Biophys Acta 1102: 119–166, 1992
Wan B, Dounen C, Duszyusky J, Salama G, Vary TC, Lanoue KF: Effect of cardiac work on electrical potential across mitochondrial membrane in perfused heart. Am J Physiol 265: H453–H460, 1993
Jurevicius J, Fischmeister R: cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by β-adrenergic agonists. Proc Natl Acad Sci USA 93: 295–299, 1996
Jurevicius J, Fischmeister R: Acetylcholine inhibits Ca2+ current by acting exclusively at a site proximal to adenylyl cyclase in frog cardiac myocytes. J Physiol 491: 669–675, 1996
Hoerter JA, Lauer C, Vassort G, Gueron M: Sustained function of normoxic hearts depleted in ATP and phosphocreatine: A P-NMR study. Am J Physiol 255: C192–C201, 1988
Neely JR, Grotyohann LW: Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts. Circ Res 55: 816–824, 1984
Mahler M: First-order kinetics of muscle oxygen consumption, and an equivalent proportionality between Qo2 and phosphorylcreatine level. J Gen Physiol 86: 135–165, 1985
Daut J: The living cell as energy-transducing machine. A minimal model of myocardial metabolism. Biochim Biophys Acta 895: 41–62, 1987
Sahlin K: Control of energetic processes in contracting human skeletal muscle. Biochem Exer 19: 353–358, 1991
Meyer RA, Foley JM: Cellular processes integrating the metabolic response to exercise. In: LB Rowell, JT Shepherd (eds). American Physiological Society Handbook of Physiology. Integration of Motor, Circulatory, Respiratory and Metabolic Control during Exercise. 1996, pp 841–868
Veksler VI, Kuznetsov AV, Anflous K, Mateo P, van Deursen J, Wieringa B, Ventura-Clapier R: Muscle creatine kinase. Cardiac and skeletal muscle exhibit tissue-specific adaptation of the mitochondrial function. J Biol Chem 270: 19921–19929, 1995
McCormack JG, England PJ: Ruthenium red inhibits the activation of pyruvate dehydrogenase caused by positive inotropic agents in the perfused heart. Biochem J 214: 581–589, 1983
Hoerter JA, Ventura-Clapier R, Kuznetsov AV: Compartmentation of creatine kinases during perinatal development of mammalian heart. Mol Cell Biochem 133/134: 277–286, 1994
Matsumoto Y, Kaneko M, Kobayashi A, Fujise Y, Yamazaki N: Creatine kinase kinetics in diabetic cardiomyopathy. Am J Physiol 268: E1070–E1076, 1995
Hamman BL, Bittl JA, Jacobus WE, Allen PD, Spencer RS, Tian R, Ingwall JS: Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts. Heart Circ Physiol 38: H1030–H1036, 1995
Tian R, Ingwall JS: Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol 270: H1207–H1216, 1996
Kapelko VI, Kupriyanov VV, Novikova NA, Lakomkin VL, Steinschneider AY, Severina MY, Veksler VI, Saks VA: The cardiac contractile failure induced by chronic creatine and phosphocreatine deficiency. J Mol Cell Cardiol 20: 465–479, 1988
Zweier JL, Jacobus WE, Korecky B, Brandejs-Barry: Bioenergetic consequences of cardiac phosphocreatine depletion induced by creatine analog feeding. J Biol Chem 266: 20296–20304, 1991
van Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P, ter Laak H, Wieringa B: Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell 74: 621–631, 1993
Steeghs K, Benders A, Oerlemans F, de Haan A, Heerschap A, Ruitenbeek W, Jost C, van Deursen J, Perrymann B, Pette D, Bruckwilder M, Koudijs J, Jap P, Veerkamp Wieringa B: Altered Ca2+ responses in muscles with combined mitochondrial and cytosolic creatine kinase deficiencies. Cell 89: 93–103, 1997
Neubauer S, Horn M, Naumann A, Tian R, Hu K, Laser M, Friedrich J, Gaudron, Schnackerz K, Ingwall JS, Ertl G: Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest 95: 1092–1100, 1995
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Saks, V., Dos Santos, P., Gellerich, F.N. et al. Quantitative studies of enzyme-substrate compartmentation, functional coupling and metabolic channelling in muscle cells. Mol Cell Biochem 184, 291–307 (1998). https://doi.org/10.1023/A:1006828106322
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DOI: https://doi.org/10.1023/A:1006828106322