title: Mitochondrial metabolism of pyruvate is required for its enhancement of cardiac function and energetics.
abstract: Pyruvate augmentation of contractile function and cytosolic free energy of ATP hydrolysis in myocardium could result from pyruvate catabolism in the mitochondria or from increased ratio of the cytosolic NAD-/NADH redox couple via the lactate dehydrogenase equilibrium.
  
  
  OBJECTIVE
  To test the hypothesis that cytosolic oxidation by pyruvate is sufficient to increase cardiac function and energetics.
  
  
  METHODS
  Isolated working guinea-pig hearts received 0.2 mM octanoate +/- 2.5 mM pyruvate as fuels. alpha-Cyano-3-hydroxycinnamate (COHC, 0.6 mM) was administered to selectively inhibit mitochondrial pyruvate uptake without inhibiting pyruvate's cytosolic redox effects or octanoate oxidation. The effects of pyruvate and COHC on sarcoplasmic reticular- Ca2+ handling were examined in 45Ca-loaded hearts.
  
  
  RESULTS
  Pyruvate increased left ventricular stroke work and power 40%, mechanical efficiency 29%, and cytosolic ATP phosphorylation potential nearly fourfold. 14CO2 formation from [1-14C]pyruvate was inhibited 65% by COHC, and octanoate oxidation, i.e. 14CO2 formation from [1-14C]octanoate, concomitantly increased threefold. COHC prevented pyruvate enhancement of left ventricular function, mechanical efficiency and cytosolic phosphorylation potential, but did not alter respective levels in pyruvate-free control hearts and augmented cytosolic oxidation by pyruvate. Pyruvate increased sarcoplasmic reticular Ca2+ turnover, i.e. Ca2+ uptake and release, as indicated by 62% decrease in caffeine-induced 45Ca release following 40 min 45Ca washout (P < 0.01). In presence of COHC, pyruvate did not lower caffeine-induced 45Ca release; thus. COHC abrogated pyruvate enhancement of Ca2+ turnover (P < 0.001).
  
  
  CONCLUSIONS
  Pyruvate oxidation of cytosolic redox state is not sufficient to increase cardiac function, cytosolic energetics and sarcoplasmic reticular Ca2+ turnover when mitochondrial pyruvate transport is disabled; thus, mitochondrial metabolism of pyruvate is essential for its metabolic inotropism.
authors.affiliation: Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth 76107-2699, USA. malletr@hsc.unt.edu
authors.forename: R T
authors.initials: RT
authors.lastname: Mallet
authors.forename: J
authors.initials: J
authors.lastname: Sun
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism / Q000494:pharmacology; D003373:Coumaric Acids / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D006168:Guinea Pigs; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction; D010477:Perfusion; D010766:Phosphorylation; D019289:Pyruvic Acid / Q000378:metabolism* / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013395:Sucrose / Q000378:metabolism
chemical_list: D002210:Caprylates; D003373:Coumaric Acids; C007175:alpha-cyano-4-hydroxycinnamate; D013395:Sucrose; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D002118:Calcium