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Circulation Research NOVEMBER VOL. 37 1975 NO. 5 An Official Journal of the American Heart Association Brief Reviews The Metabolic Significance of the Malate-Aspartate Cycle in Heart By Brian Safer Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 • Under physiological conditions, the energy requirements of the heart are met primarily by the oxidation of fatty acids, glucose, and lactate (1, 2). Initially, during the metabolism of glucose and lactate, the coenzyme NAD is reduced to NADH and pyruvate is formed in the cytosolic compartment 1 of the myocardial cell. Subsequent entry of pyruvate into the mitochondria for oxidative metabolism in the citric acid cycle requires an equivalent oxidation of cytosolic NADH by the mitochondrial electron transport chain, which regenerates NAD. However, direct transfer of the reduced coenzyme NADH to the respiratory chain is prevented by a selective permeability barrier across the inner mitochondrial membrane to NADH as well as other metabolic intermediates (3, 4). Although several indirect shuttle mechanisms have been proposed (5-7), current evidence indicates that the reducing equivalents formed in the reduction of cytosolic NAD to NADH are indirectly carried into the mitochondrial compartment of the heart and other tissues by metabolic anions of the malate-aspartate cycle (8-11). In addition, interaction of the malate-aspartate cycle with the citric acid cycle, through key common metabolic intermediates, may provide a major mechanism by which coordination of mitochondrial and cytosolic energy metabolism is achieved in the myocardium (9, 12, 13). OXIDATION OF CYTOSOLIC NADH BY THE MALATE-ASPARTATE CYCLE In the malate-aspartate cycle, cytosolic NADH generated at either glyceraldehyde-3-phosphate From the Molecular Hematology Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland 20014. 'The term cytosolic compartment designates the intracellular space exclusive of the water-permeable space enclosed by the inner mitochondrial membrane. Circulation Research, Vol. 37, November 1975 dehydrogenase or lactate dehydrogenase is oxidized back to NAD by the reduction of oxaloacetate to malate (Fig. 1). Malate then crosses the inner mitochondrial membrane to enter the mitochondrial matrix where oxidation of malate regenerates oxaloacetate and NADH. In this manner, cytosolic reducing equivalents from NADH are indirectly transferred via malate to the respiratory chain for oxidation. The return of oxaloacetate thus formed in the mitochondrial compartment to the cytosolic compartment, which completes the malate-aspartate cycle, appears to be limited by a selective impermeability of the inner mitochondrial membrane and the low intramitochondrial concentration of oxaloacetate. Instead, oxaloacetate is transaminated with glutamate in the mitochondrial compartment to form a-ketoglutarate and aspartate. Aspartate and a-ketoglutarate are able to cross the inner mitochondrial membrane, and, by the reverse transamination, oxaloacetate and glutamate are regenerated in the cytosolic compartment to complete the cycle (5, 6, 14). Distinct cytosolic and mitochondrial isoenzymes of malate dehydrogenase and aspartate aminotransferase catalyze these reactions (15). ROLE OF METABOLIC ANION EXCHANGE CARRIERS IN THE MALATE-ASPARTATE CYCLE Indirect calculations based on levels of oxidized and reduced metabolites in several tissues (16-18) suggest that, in the heart, the mitochondrial pyridine nucleotide pool is also maintained at a level considerably more reduced than that of the cytosol (the ratio of NADH to NAD is 10-100-fold higher in the mitochondria). Therefore, transfer of cytosolic reducing equivalents to the respiratory chain is energetically unfavorable and cannot occur by free diffusion of the metabolic anions of the malate527 528 SAFEF CYTOSOL GLU -, NAD — -MAL a-KG TRIOSEP \ GLU ASP ASP — II GLUCOSE Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 INNER MITOCHONDRIAL MEMBRANE MATRIX FIGURE 1 The malate-aspartate cycle. NADH formed in the cytosolic compartment of the cell is oxidized by the reduction of oxaloacetate (OAA) to malate (MAL). Malate then indirectly transfers these reducing equivalents into the mitochondrial compartment where oxaloacetate and NADH are regenerated. For steady-state operation of the malate-aspartate cycle, oxaloacetate must be continuously returned to the cytosolic compartment. Because of its low concentration in the mitochondria and the relative impermeability of the mitochondrial membrane to oxaloacetate, this transfer is also indirectly accomplished by transamination with glutamate (GLU) to form a-ketoglutarate (a-KG) and aspartate (ASP). These substances are then transferred to the cytosolic compartment where the reverse transamination regenerates oxaloacetate and glutamate. Distinct mitochondrial and cytosolic isoenzymes catalyze these reactions. A specific electroneutral carrier system catalyzes the equal and opposite exchange of malate and a-ketoglutarate (I). The aspartate-glutamate antiport system (II), in contrast, appears to be electrogenic. By directly utilizing the free energy of the electrochemical gradient established by electron transport, cytosolic NADH can be indirectly transferred into the mitochondrial compartment against a NADH-NAD potential gradient. LAC = lactate, PYR = pyruvate, and TRIOSE-P = glyceraldehyde-3-P and a-glycerophosphate. aspartate cycle across the inner mitochondrial membrane. It has been demonstrated, however, that such anion exchange is mediated by specific carriers,2 some of which may be energy linked (14, 19-21). In coupled mitochondria, transfer of electrons in the respiratory chain results in the production of a small pH gradient (< 0.5 pH units, alkaline inside) and an electrical potential gradient (< 250 mv, negative inside) across the inner membrane. Recent evidence suggests that the 2 Mitochondrial anion translocators are classified as either antiport systems which exchange ions or symport systems which promote unidirectional coupled transfer of ions across the inner mitochondrial membrane. Electroneutral carriers do not alter charge separation across this membrane, but electrogenic carriers can directly utilize the electrochemical potential gradient established by electron transport to energize transport of metabolic anions (14-16). anion exchange carriers can directly utilize thes potential gradients to drive the malate-aspartai cycle (19, 22-26). During the steady-state operation of the malatt aspartate cycle, malate is exchanged stoichiometr cally for a-ketoglutarate across the inner mitochor drial membrane by a specific electroneutral ant port system (27) according to the net chemici gradient. It had been proposed that this malate-c ketoglutarate exchange carrier (labeled I in Fig. '. is driven by the pH gradient across the inn* mitochondrial membrane (19). However, althoug this mechanism is feasible in the liver, it cannot t the primary energy source for the malate-aspartai cycle in the myocardium, since the activity of tr malate-phosphate exchange carrier (also require for utilization of the pH gradient) is low in hea Circulation Research, Vol. 37, November 19 MALATE-ASPARTATE CYCLE Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 mitochondria (21, 22, 27, 28). In addition, the pH gradient (alkaline inside) established by electron transport opposes transport of malate and a-ketoglutarate in the direction required for removal of cytosolic reducing equivalents. The primary energy source for the malate-aspartate cycle appears to be the aspartate-glutamate antiport system. In contrast to the electroneutral malate-a-ketoglutarate antiport system, exchange of glutamate and aspartate appears to be electrogenie due to the carrier-mediated cotransport of one proton per glutamate molecule. Thus, a net transfer of charge accompanies this exchange, which permits direct utilization by the aspartateglutamate exchange carrier (labeled II in Fig. 1) of the potential gradient established by the outwarddirected proton pump that is coupled to electron transport (24-26). Expenditure of energy to maintain the electrochemical gradient across the inner mitochondrial membrane during electron transfer may therefore provide the energy required for uphill transfer of reducing equivalents by the malate-aspartate cycle against an NADH-NAD potential gradient (29). In addition, since this carrier can only exchange intramitochondrial aspartate for extramitochondrial glutamate (24-26, 30, 31), transfer of reducing equivalents is permitted only from the cytosolic to the mitochondrial compartment. INTERACTION OF THE MALATE-ASPARTATE AND CITRIC ACID CYCLES AND NONUNIFORM CITRIC ACID CYCLE FLUX Through shared metabolic intermediates, the malate-aspartate cycle interacts directly with the citric acid cycle in the region of citrate synthetase and a-ketoglutarate dehydrogenase. As a result, the flux of substrates through different portions of the citric acid cycle may not be equal but is modulated by the relative rates of reaction at two metabolic branch points indicated by the asterisks in Figure 2 (12, 13). The two key enzymes which determine the extent of nonuniform flux throughout the citric acid cycle are a-ketoglutarate dehydrogenase and mitochondrial aspartate aminotransferase. Entry of a-ketoglutarate into the second half of the citric acid cycle (labeled CAC II in Fig. 2) or diversion into the malate-aspartate cycle appears to be regulated by the flux through a-ketoglutarate dehydrogenase. The activity of a-ketoglutarate dehydrogenase is primarily regulated by the succinyl-CoA-CoA and NADH-NAD ratios (32, 33); an increased ratio results in inhibition. The succinylCoA-CoA ratio is indirectly regulated by the ATPCirculation Research, Vol. 37, November 1975 529 ADP ratio via substrate-level phosphorylation (at succinate thiokinase). The NADH-NAD ratio generally reflects the rate of electron transport. Therefore, partition of a-ketoglutarate flux into the citric acid cycle or the malate-aspartate cycle in response to the energy state of the myocardium is directed by the activity of a-ketoglutarate dehydrogenase (9, 32). Similarly, oxaloacetate can either enter the first half of the citric acid cycle (labeled CAC I in Fig. 2) or bypass it by undergoing transamination with glutamate. Flux through a second enzyme, aspartate aminotransferase, appears to indirectly regulate this partition of oxaloacetate. Flux through this enzyme is dependent on the availability of both oxaloacetate and glutamate. The energylinked glutamate-aspartate exchange carrier, by regulating transfer of glutamate (and aspartate) across the inner mitochondrial membrane, may therefore be primarily responsible for determining whether oxaloacetate bypasses the first part of the citric acid cycle. The rate of glutamate transfer by this carrier is also dependent on the ratio of the concentrations of glutamate and aspartate in the cytosol (9, 30, 34). Thus, the metabolic fate of oxaloacetate is determined not only by reactions of the citric acid cycle in the mitochondrial compartment but also by the cytosolic levels of key metabolites shared by the malate-aspartate cycle. Control by these two enzymes, a-ketoglutarate dehydrogenase and aspartate aminotransferase (via the aspartate-glutamate carrier), allows flux in span I and span II of the citric acid cycle to be transiently dissimilar. As subsequently discussed, such transient disruptions of uniform flux are absolutely required for rapid alterations of myocardial citric acid cycle intermediate levels. ROLE OF THE MALATE-ASPARTATE CYCLE IN THE COORDINATION OF GLYCOLYTIC AND CITRIC ACID FLUXES In addition to providing a mechanism for the oxidation of cytosolic NADH, the malate-aspartate cycle is required to coordinate mitochondrial and cytosolic metabolism in the heart. Under a wide variety of metabolic conditions, balanced glycolytic and citric acid cycle fluxes allow more efficient oxidative metabolism of carbohydrate fuels. Direct feedback inhibition of glycolysis at phosphofructokinase by citrate and ATP has generally been accepted as the primary mechanism for this control (35, 36). Although this mechanism is supported by kinetic studies of isolated enzymes and changes in the tissue levels of metabolic intermediates following changes in flux (37), any direct regulation of 530 SAFER CYTOSOL MAL LAC L PYR t >s t MAnu NADH * OAA a-KG TRIOSE-P . PYR: GLU GLUCOSE a-KG ISOCIT Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 V INNER MITOCHONDRIAL MEMBRANE MATRIX CIT FIGURE 2 Interactions of the malate-aspartate cycle, the glycolytic pathway, and the citric acid cycle which allow indirect oxidation of cytosolic NADH, rapid alteration of citric acid cycle intermediate levels, and fine coordination of cytosolic and mitochondrial energy metabolism. The malate-a-ketoglutarate and aspartate-glutamate exchange carriers, labeled I and II, respectively, are located in the inner mitochondrial membrane. Two key metabolic branch points at citrate synthetase and a-ketoglutarate dehydrogenase are identified by asterisks. By partitioning total metabolic flux between the malate-aspartate and citric acid cycles, transiently dissimilar fluxes are allowed in the two functionally distinct spans of the citric acid cycle (13) designated in the figure as CAC I and CAC II. The nonuniform citric acid cycle flux in the heart permitted by these two spans is required for rapid changes in citric acid cycle intermediate levels. A-i indicate key enzymes in these pathways, (a) = glyceraldehyde-3-phosphate dehydrogenase, (b) = lactate dehydrogenase, (c) = malate dehydrogenase, (d) = aspartate aminotransferase, (e) = citrate synthetase, (f) = aconitase, (g) = isocitrate dehydrogenase, (h) = a-ketoglutarate dehydrogenase, and (i) = alanine aminotransferase. LAC = lactate, PYR, = pyruvate, MAL = malate, OAA = oxaloacetate, a-KG = a-ketoglutarate, GLU = glutamate, ASP = aspartate, ALA = alanine, ISOCIT = isocitrate, CIT = citrate, AcCoA = acetyl coenzyme A, and TRIOSE-P = glyceraldehyde-3-Pand a-glycerophosphate. glycolysis by citrate in the heart must reconcile the virtually complete inability of citrate formed in the mitochondrial compartment to cross the inner mitochondrial membrane (21, 38) and affect phosphofructokinase in the cytosol. By linking the citric acid cycle within the mitochondria to the cytosolic isoenzymes of alanine aminotransferase, isocitrate dehydrogenase, and aconitase, the malate-aspartate cycle appears to provide a mechanism for rapid changes in citric acid cycle intermediate levels in the cytosolic compartment (Fig. 2). This interaction allows glycolytic flux to be responsive to the redox state of pyridine nucleotides, the phosphorylation state of adenine nucleotides, and, thus, the energy state of the heart (8, 9, 12, 39). MECHANISM FOR THE ALTERATION OF CITRIC ACID CYCLE INTERMEDIATE LEVELS IN THE HEART In addition to being required for changes ir cytosolic citrate levels, rapid changes in total citrii acid cycle intermediate levels in the heart appea to require interaction of the citric acid and malate aspartate cycles. Increased tissue levels of citrati cannot be the direct result of an increased rate o acetyl-CoA entry into the citric acid cycle, sino two molecules of carbon dioxide are formed pe cycle turnover and additional oxaloacetate is no generated. Enzymes required for the carboxylatioi of pyruvate or acetate are also absent in the hear (13, 40). Although tissue levels of total citric acii cycle intermediates and aspartate appear to hav Circulation Research, Vol. 37, November 19? 531 MALATE-ASPARTATE CYCLE an inverse relationship to one another, transamination of aspartate cannot directly increase the size of the citric acid cycle intermediate pool, since a-ketoglutarate is removed as glutamate in this reaction. However, the coupled transamination of aspartate and glutamate by (1) aspartate aminotransferase of the malate-aspartate cycle and (2) alanine aminotransferase is able to form oxaloacetate in the cytosolic compartment from two metabolic intermediates that are not directly part of the citric acid cycle intermediate pool (12, 13, 41): Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 (1) Aspartate + a-Ketoglutarate •<—»• Oxaloacetate + Glutamate (2) Glutamate + Pyruvate-.—>• Alanine + a-Ketoglutarate SUM Aspartate + Pyruvater—>• Oxaloacetate + Alanine For example, provision of glucose to a substratedeficient heart (12) leads to an increase in the total citric acid cycle intermediate pool by the following interaction of the metabolic pathways presented in Figure 2. An increased cytosolic NADH-NAD ratio, resulting from greater glycolytic flux, leads to the rapid reduction of cytosolic oxaloacetate to malate. This first step results in a displacement of the equilibrium at cytosolic aspartate aminotransferase; by increasing cytosolic glutamate, this displacement is in turn transmitted to alanine aminotransferase. This coupled transamination is responsible for a net gain in the total tissue citric acid cycle intermediate pool. Initially, however, the rate of oxaloacetate formation is severely limited by the availability of cytosolic a-ketoglutarate required for transamination with aspartate. Additional a-ketoglutarate is provided by an increased rate of production in the first span of the citric acid cycle relative to its rate of entry into the second span. As the result of (1) greater availability of acetyl-CoA secondary to increased glycolytic flux and (2) limiting mitochondrial glutamate, the increased rate of mitochondrial oxaloacetate formation is primarily partitioned toward formation of a-ketoglutarate in the first span of the citric acid cycle. However, because a-ketoglutarate is exchanged stoichiometrically for malate across the inner mitochondrial membrane and both the intramitochondrial NADH-NAD and ATP-ADP ratios increase (thereby inhibiting a-ketoglutarate dehydrogenase), this increased mitochondrial a-ketoglutarate production is primarily diverted to the cytosol. Thus, flux in span I of Circulation Research, Vol. 37, November 1975 the citric acid cycle becomes transient^' greater than that in span II. a-Ketoglutarate transferred to the cytosol in this manner can then be directly utilized for transamination with aspartate. Alternatively, a-ketoglutarate can be reduced to isocitrate by NADP-linked isocitrate dehydrogenase, with citrate then being formed via aconitase. In this manner, both the total tissue content and the intracellular distribution of citric acid cycle intermediates can be altered. Once equilib. ; um is reestablished at cytosolic aspartate aminotransferase, the tissue level of citric acid cycle intermediates stabilizes to a new steady-state level and fluxes in the citric acid and malate-aspartate cycles become uniform. Since all of these enzymes present in the cytosolic compartment are fully reversible, changes in the oxidationreduction state of cytosolic pyridine nucleotides and the metabolic substrate supply can increase or decrease the tissue levels of citric acid cycle intermediates in this manner. SIGNIFICANCE OF THE MALATEASPARTATE CYCLE The central role of the malate-aspartate cycle in myocardial energy metabolism raises a number of important questions as to its role in the pathogenesis of and the compensatory response to a number of disorders of myocardial function. It has been demonstrated, for example, that generalized inhibition of the malate-aspartate cycle can produce idiopathic lactic acidosis (8, 42, 43). Such inhibition in the heart can also have profound direct and indirect effects on contractility, since both excitation-contraction coupling and the malate-aspartate cycle appear to be inhibited by acidosis (44-49). By decreasing the oxidative metabolism of glucose, which requires the malate-aspartate cycle, localized acidosis can also contribute to contractile failure and affect survival of the ischemic myocardium. Although such suggestions are highly speculative at the present time, further research in these areas appears to be warranted. Acknowledgment I gratefully acknowledge the support, encouragement, and useful discussions provided by Dr. John R. Williamson and his associates at the Johnson Research Foundation, who contributed significantly to the organization and the scope of this review. References 1. BINC. RJ: Cardiac metabolism. Physiol Rev 45:171-213, 1965 2. OPIE LH: Metabolism of the heart in health and disease. Part I. Am Heart J 76:685-698, 1968 3. LEHNINGER AL: Phosphorylation coupled to oxidation of SAFER 532 dihydro-diphosphopyridine nucleotides. J Biol Chem 190:345-359, 1951 4. PURVIS JL, LOWENSTEIN JM: Relation between intra- and extramitochondrial pyridine nucleotides. J Biol Chem 236:2794-2803, 1961 5. BORST P: Hydrogen transport and transport metabolites. In Functionelle und Morphologische Organisation der Zelle, edited by P Karlson. Berlin, Springer-Verlag, 1963. pp 137-158 20. KLINGENBERG M: Metabolite transport in mitochondria: Ar example for intracellular membrane function. In Essay; in Biochemistry, vol 6, edited by PN Campbell and I Dickens. London, Academic Press, 1970, pp 119-159 21. SLUSE FE, MEIJER AJ, TAGER JM: Anion translocators in rai heart mitochondria. FEBS Lett 18:149-153, 1971 22. PALMIERI F, GENCHI G, QUAGLIARIELLO E: Control mech lebendigen Organisation. Angew Chem 70:552-570, 1958 anisms of anion distribution across the mitochondria membrane. Experientia (Suppl] 18:505-512, 1971 23. MITCHELL P: Chemiosmotic Coupling and Energy Transduc tion. Bodwin, Cornwall, Glynn Res. Ltd., 1968 7. WHEREAT AF, ORISHIMO MW, NELSON J, PHILLIPS SJ: Loca- 24. LANOUE KF, MEIJER AJ, BROUWER A: Evidence for electro tion of different synthetic systems for fatty acids in inner and outer mitochondrial membranes from rabbit heart. J Biol Chem 244:6498-6506, 1969 genie aspartate transport in rat liver mitochondria. Arcl Biochem Biophys 161:544-550, 1974 6. BUCHER TH, KLINGENHEKG M: Wege des Wasserstoff's in der 8. SAFER B, SMITH CM, WILLIAMSON JR: Control of the trans- port of reducing equivalents across the mitochondrial membrane in perfused rat heart. J Mol Cell Cardiol 2:111-124, 1971 9. WILLIAMSON JR, SAFER B, LANOUE KF, SMITH CM, WALAJTYS Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 E: Mitochondrial-cytosolic interactions in cardiac tissue: Role of the malate-aspartate cycle in the removal of glycolytic NADH from the cytosol. In Symposia Soc Exp Biol, vol 27, Cambridge, England, Cambridge University Press, 1973, p 248 and 281 10. ANDERSON JH, NICKLAS WJ, BLANK B, REFINO C, WILLIAMSON JR: Transfer of carbon and hydrogen across the mitochondrial membrane in the control of gluconeogenesis. In Regulation of Gluconeogenesis: 9th Conference of the Gesellschaft fur Biologische Chemie, edited by HD Soling and B Willms. Stuttgart, G. Thieme-Verlag, 1971, pp 293-315 11. ROGNSTAD R, KATZ J: Gluconeogenesis in the kidney cortex: Effects of D-malate and aminooxyacetate. Biochem J 116:483-491, 1970 12. SAFER B, WILLIAMSON JR: Mitochondrial-cytosolic interac- tions in perfused rat heart: Role of coupled transamination in repletion of citric acid cycle intermediates. J Biol Chem 248:2570-2579, 1973 13. RANDLE PJ, ENGLAND PJ, DENTON RM: Control of the tri- carboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J 117:677695, 1970 14. CHAPPELL JB: Systems used for the transport of substrates into mitochondria. Br Med Bull 24:150-157, 1968 15. GREVILLE GD: Intracellular compartmentation and the citric acid cycle. In Citric Acid Control and Compartmentation, edited by JM Lowenstein. New York, Marcel Dekker, 1969, pp 1-64 16. WILLIAMSON DH, LUND P, KREBS HA: Redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J 103:514-527, 1967 17. KREBS HA, VEECH RL: Pyridine nucleotide interrelations. In The Energy Level and Metabolic Control in Mitochondria, edited by S Papa, JM Tager, E Quagliariello, and EC Slater. Bari, Italy, Adriatica Editrice, 1969, pp 329-382 25. LANOUE KF, BRYLA J, BASSETT DJP: Energy-driven aspar tate efflux from heart and liver mitochondria. J Bio Chem 249:7514-7521, 1974 26. LANOUE KF, TISCHLER ME: Electrogenic characteristics o the mitochondrial glutamate-aspartate antiporter. J Bio Chem 249:7522-7528, 1974 27. SLUSE FE, RANSON M, LIEBECQ C: Mechanism of thi exchanges catalyzed by the oxoglutarate translocator o rat heart mitochondria. Eur J Biochem 25:207-217, 1972 28. SCOTT KM, JURKOWITZ M, BRIERLY GP: Ion transport b; heart mitochondria: XXVI. Carrier-mediated anioi transport by isolated beef heart mitochondria. Arcl Biochem Biophys 153:682-694, 1972 29. LANOUE KF, WILLIAMSON JR: Interrelationships betweei malate-aspartate shuttle and citric acid cycle in rat hear mitochondria. Metabolism 20:119-140, 1971 30. LANOUE KF, WALAJTYS El, WILLIAMSON JR: Regulation o glutamate metabolism and interactions with the citri acid cycle in rat heart mitochondria. J Biol Cher 248:7171-7183, 1973 31. Azzi A, CHAPPELL JB, ROBINSON BH: Penetration of th mitochondrial membrane by glutamate and aspartate Biochem Biophys Res Commun 28:148-152, 1967 32. SMITH CM, BRYLA J, WILLIAMSON JR: Regulation of mito chondrial a-ketoglutarate metabolism. J Biol Cher 249:1497-1505, 1974 33. GARLAND PB: Some kinetic properties of pig heart oxoglutai ate dehydrogenase that provide a basis for the control c enzyme activity and also a stoichiometric assay fc coenzyme A in tissue extracts. Biochem J 92:10c-12c 1964 34. WILLIAMSON JR, SMITH CM, LANOUE KF, BRYLA J: Feedbac control of the citric acid cycle. In Energy Metabolism an the Regulation of Metabolic Processes in Mitochondrif edited by MA Mehlman and RW Hanson. New Yorl Academic Press, 1972, pp 185-210 35. PASSONNEAU JV, LOWRY OH: Phosphofructokinase and th control of the citric acid cycle. Biochem Biophys Re Commun 13:372-379, 1963 36. SCRUTTON MC, UTTER MF: Regulation of glycolysis an anisms of gluconeogenesis and ketogenesis: I. Effects of oleate on gluconeogenesis in perfused rat liver. J Biol Chem 244:4607-4616, 1969 gluconeogenesis in animal tissues. Annu Rev Biochei 37:249-302, 1968 37. WILLIAMSON JR: Glycolytic control mechanisms: I. Inhib tion of glycolysis by acetate and pyruvate in the isolate perfused rat heart. J Biol Chem 240:2308-2321, 1965 38. ENGLAND PJ, ROBINSON BH: Permeability of rat heart mit< chondria to citrate. Biochem J 112:8p, 1969 19. PAPA S, LOFRUMENTO NE, QUAGLIARIELLO E, MEIJER AJ, 39. STUBBS M, VEECH RL, KREBS HA: Control of the redox stat TAGER JM: Coupling mechanisms in anionic substrate transport across the inner membrane of rat liver mitochondria. Bioenergetics 1:287-307, 1970 of the nicotinamide-adenine dinucleotide couple in n liver cytoplasm. Biochem J 126:59-65, 1972 40. BOWMAN RH: Effects of diabetes, fatty acids and ketor 18. WILLIAMSON JR, BROWNING ET, SCHOLZ R: Control mech- Circulation Research, Vol. 37, November 197 MALATE ASPARTATE CYCLE bodies on tricarboxylic acid cycle metabolism in perfused rat heart. J Biol Chem 241:3041-3048, 1966 DAVIS EJ, LIN RC, CHAO DL: Sources and disposition of aerobically generated intermediates in heart muscle. In Energy Metabolism and the Regulation of Metabolic Processes in Mitochondria, edited by MA Mehlman and RW Hanson. New York, Academic Press, 1972, pp 211-238 12. SUSSMAN KF, ALFREY A, KIRSCH WM, ZWEIG P, GELIG P, MESSNER F: Chronic lactic acidosis in an adult: A new syndrome associated with an altered redox state of certain NAD/NADH coupled reactions. Am J Med 48:104-112, 1970 RELMAN AS: Metabolic consequences of acid-base disorders. Kidney Int 1:347-359, 1972 Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 rculation Research, Vol. 37, November 1975 533 44. HEMINGTON JG: Inhibition of the malate-aspartate cycle in rat liver and heart mitochondria by low pH (abstr). Fed Proc 32:557, 1973 45. SAFER B, DAVIES RE: Effects of [H+] on physiological and biochemical function of heart (abstr). Fed Proc 32:449, 1973 46. SAFER B: Mitochondrial-cytosolic interactions in rat heart. Ph.D. Dissertation, University of Pennsylvania. University Microfilms, Ann Arbor, Michigan, 1973 47. KATZ AM, HECHT HH: The early pump failure of the ischemic heart. Am J Med 47:497-502, 1969 48. VAUGHAN WILLIAMS EM, WHYTE JM: Chemosensitivity of cardiac muscle. J Physiol (Lond) 189:119-137, 1967 49. LORKOVIC H: Influence of changes in pH on the mechanical activity of cardiac muscle. Circ Res 19:711-720, 1966 The Metabolic Significance of the Malate-Aspartate Cycle in Heart. B Safer Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 Circ Res. 1975;37:527-533 doi: 10.1161/01.RES.37.5.527 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/37/5/527.citation Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/