Ischemic Alterations in Mitochondrial Calcium Transport Kinetics

An Indicator of Matrix Sulfhydryl Redox State
  • Jeanie B. McMillin
  • Daniel F. Pauly
  • Kiminori Kajiyama
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


Cardiac function and energetics are intimately linked to an extracellular source of activator calcium. The levels of cytosolic free calcium available to the contractile proteins are precisely regulated by a variety of ion pump and channel proteins present in the cell membrane and sarcoplasmic reticulum. Low to moderate levels of calcium entry across the sarcolemma results in positive inotropy with increases in systolic pressure. However, further increase in calcium influx has only modest effects on systolic function, and diastolic pressure becomes elevated. High concentrations of cell calcium reduce systolic pressure from its optimal levels and increase diastolic pressure even more. It is now believed that the calcium-dependent “diastolic tonus” results from calcium loading and spontaneous release from the sarcoplasmic reticulum (Lakattaet al., 1986). Therefore, calcium appears to play a central role in aberrant cardiac function. In model studies of cardiac disease, accumulation of cellular calcium following 30 min of ischemia with reflow is also associated with a large change in diastolic pressure and low rates of systolic pressure development (Burtonet al., 1986). Both conditions are diagnostic of a high calcium load. The sequence of events which leads to postischemic calcium entry is not well defined; however, an observed ischemic increase in intracellular sodium is thought to activate sarcolemmal sodium-calcium exchange with large increases in cellular calcium influx (Grinwald, 1982). Decreases in sarcolemmal Na+ ,K+ -ATPase activity in early ischemia (Bersohnet al., 1982) could be the basis for the increases in intracellular Na+ . However, other investigators observed only small changes in activity associated with irreversible cell injury (Schwartzet al., 1973). Calcium overload during reperfusion of reversibly injured, acutely ischemic tissue could explain the prolonged contractile abnormalities which accompany the reperfusion period (McMillin-Woodet al., 1979).


Sarcoplasmic Reticulum Calcium Uptake Calcium Channel Antagonist Cellular Calcium Mitochondrial Calcium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Beatrice, M. C., Stiers, D. L., and Pfeiffer, D. R., 1984, The role of glutathione in the retention of Ca2+ by liver mitochondria, J. Biol. Chem. 259:1279–1287.PubMedGoogle Scholar
  2. Bersohn, M. M., Philipson, K. D., and Fukushima, J. Y., 1982, Sodium-calcium exchange and sarcolemmal enzymes in ischemic rabbit hearts, Am. J. Physiol. 242:C288–C295.PubMedGoogle Scholar
  3. Burton, K. P., Buja, L. M., Willerson, J. T., and Chien, K. R., 1986, Accumulation of arachidonate in triacylglycerols and unesterified fatty acids during ischemia and reflow in the isolated rat heart, Am. J. Pathol. 124:238–245.PubMedGoogle Scholar
  4. Chien, K. R., Han, A., Sen, A., Buja, L. A., and Willerson, J. T., 1984, Accumulation of unesterified arachidonic acid in ischemic canine myocardium: Relationship to a phosphatidylcholine deacyla-tion-reacylation cycle and the depletion of membrane phospholipids, Circ. Res. 54:313–322.PubMedGoogle Scholar
  5. Chien, K. R., Sen, A., Reynolds, R., Chang, A., Kim, Y., Gunn, M. D., Buja, L. M., and Willerson, J. T., 1985, Release of arachidonate from membrane phospholipids in cultured neonatal rat myo-cardial cells during adenosine triphosphate depletion. Correlation with the progression of cell injury, J. Clin. Invest. 75:1770–1780.PubMedCrossRefGoogle Scholar
  6. Corr, P. B., Gross, R. W., and Sobel, B. E., 1984, Amphipathic metabolites and membrane dysfunction in ischemic myocardium, Circ. Res. 55:135–154.PubMedGoogle Scholar
  7. Fiskum, G., and Lehninger, A. L., 1982, Mitochondrial regulation of intracellular calcium, in: Calcium and Cell Function ,Vol. 2 (W. Y. Cheung, ed.), Academic Press, New York, pp. 39–80.Google Scholar
  8. Grinwald, P. M., 1982, Calcium uptake during post-ischemic reperfusion in the isolated rat heart: Influence of extracellular sodium, J. Mol. Cell. Cardiol. 14:359–365.PubMedCrossRefGoogle Scholar
  9. Gross, R. W., Ahumada, G. G., and Sobel, B. E., 1984, Cytosolic lysophospholipase in cardiac myocytes and its inhibition by 1-palmitoylcarnitine, Am. J. Physiol. l5:C266–C270.Google Scholar
  10. Hansford, R. G., 1985, Relation between mitochondrial calcium transport and control of energy metabolism, in: Rev. Physiol. Biochem. Pharmacol. ,Vol. 102, Springer-Verlag, New York, pp. 1–72.Google Scholar
  11. Herdson, P. B., Sommers, N. H., and Jennings, R. B., 1963, A comparative study of the fine structure of normal and ischemic dog myocardium with special reference to early changes following temporary occlusion of a coronary artery, Am. J. Pathol. 46:367–386.Google Scholar
  12. Hoerter, J. A., Miceli, M. V., Renlund, D. G., Jacobus, W. E., Gerstenblith, G., and Lakatta, E. G., 1986, A phosphorus-31 nuclear magnetic resonance study of the metabolic, contractile and ionic consequences of induced calcium alterations in the isovolumic rat heart, Circ. Res. 58:539–551.PubMedGoogle Scholar
  13. Jennings, R. B., Kaltenbach, J. P., and Summers, H. M., 1967, Mitochondrial metabolism in ischemic injury, Arch. Pathol. 84:15–19.PubMedGoogle Scholar
  14. Jolly, S. R., Kane, W. J., Bailie, M. B., Abrams, G. D., andLucchesi, B. R., 1984, Canine myocardial reperfusion injury: Its reduction by the combined administration of Superoxide dismutase and catalase, Circ. Res. 54:277–285.PubMedGoogle Scholar
  15. Jurkowitz, M. S., Geisbuhler, T., Jung, D. W., and Brierley, G. P., 1983, Ruthenium red-sensitive and-insensitive release of Ca2+ from uncoupled heart mitochondria, Arch. Biochem. Biophys. 223:120–128.PubMedCrossRefGoogle Scholar
  16. Kajiyama, K., Pauly, D. F., Hughes, H., Yoon, S. B., Entman, M. L., and McMillin-Wood, J., 1987, Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium, Circ. Res. 61:301–310.PubMedGoogle Scholar
  17. Kellogg, E. W., and Fridovich, I., 1975, Superoxide hydrogen peroxide and singlet oxygen in per-oxidation by a xanthine oxidase system, J. Biol. Chem. 250:8812–8817.PubMedGoogle Scholar
  18. Kloner, R. A., DeBoer, L. W. V., Carlson, N., and Braunwald, E., 1982, The effect of verapamil on myocardial ultrastructure during and following release of coronary artery occlusion, Exp. Mol. Pathol. 36:277–286.PubMedCrossRefGoogle Scholar
  19. Lakatta, E. G., Capogrossi, M. C., Kort, A. A., and Stern, M. D., 1987, Functional sequelae of diastolic sarcoplasmic reticulum Ca2+ release in the myocardium, in: Diastolic Relaxation of the Heart ,Proceedings of an International Symposium (W. Grossman and B. H. Lorell, eds.), pp. 49–64, Martinez Nijhass, Boston, Mass.Google Scholar
  20. McMillin-Wood, J. B., Entman, M. L., Hanley, H. G., Lewis, R. M., Busch, U., Chang, C. H., Swain, J. A., Morgan, W. J., and Schwartz, A., 1979, Biochemical and morphological correlates of acute experimental myocardial ischemia. III. Energy producing mechanisms, Circ. Res. 44: 52–61.Google Scholar
  21. Okuyama, H., and Nojimi, S., 1965, Studies on hydrolysis of cardiolipin by snake venom phospholipase A, J. Biochem. (Tokyo) 57:529–538.Google Scholar
  22. Pinsky, W. W., Lewis, R. M. McMillin-Wood, J. B., Hara, H., Gillette, P. C., and Entman, M. L., 1981, Myocardial protection from ischemic arrest: Potassium and verapamil cardioplegia, Am. J.Physiol 240:H326–H355.PubMedGoogle Scholar
  23. Physiol 240:H326-H355. Przyklenk, R., and Kloner, R. A., 1986, Superoxide dismutase plus catalase improve contractile function in the canine model of the “stunned myocardium,” Circ. Res. 58:148–156.PubMedGoogle Scholar
  24. Renlund, D. G., Lakatta, E. G., Mellits, E. D., and Gerstenblith, G., 1985, Calcium-dependent enhancement of myocardial diastolic tone and energy utilization dissociates systolic work and oxygen consumption during low sodium perfusion, Circ. Res. 57:876–888.PubMedGoogle Scholar
  25. Schwartz, A., McMillin-Wood, J., Allen, J. C., Bornet, E. P., Entman, M. L., Goldstein, M. A., Sordahl, L. A., and Suzuki, M., 1973, Biochemical and morphological correlates of cardiac ischemia, Am. J. Cardiol 32:46–61.PubMedCrossRefGoogle Scholar
  26. Somlyo, A. P., Somlyo, A. V., Shuman, H., Scarpa, A,. Endo, M., and Inesi, G., 1981, Mitochondria do not accumulate significant Ca2+ concentrations in normal cells, in: Calcium and Phosphate Transport across Biomembrane s (F. Bronner and M. Peterlik, eds.), Academic Press, New York, pp. 87–93.Google Scholar
  27. Van der Vusse, G. J., Roemen, Th. H. M., Pringen, F. W., Coumans, W. A., and Reneman, R. S., 1982, Uptake and tissue content of fatty acids in dog myocardium under normoxic and ischemic conditions, Circ. Res. 50:538–546.PubMedGoogle Scholar
  28. Wolkowicz, P. E., and McMillin-Wood, J., 1980, Dissociation between mitochondrial calcium ion release and pyridine nucleotide oxidation, J. Biol. Chem. 255:10348–10353.PubMedGoogle Scholar
  29. Wolkowicz, P. E., Michael, L. H., Lewis, R. M., and McMillin-Wood, J., 1983, Sodium-calcium exchange in dog heart mitochondria: Effects of ischemia and verapamil, Am. J. Physiol. 244: H644–H65l.PubMedGoogle Scholar
  30. Yoon, S. B., McMillin-Wood, J. B., Michael, L. H., Lewis, R. M., and Entman, M. L., 1985, Protection of canine cardiac mitochondrial function by verapamil cardioplegia during ischemic arrest, Circ. Res. 56:704–708.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Jeanie B. McMillin
    • 1
    • 2
  • Daniel F. Pauly
    • 1
    • 2
  • Kiminori Kajiyama
    • 1
    • 2
  1. 1.Department of Medicine, Division of Cardiovascular DiseaseUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Medicine, Section of Cardiovascular SciencesBaylor College of MedicineHoustonUSA

Personalised recommendations