Aging and Dietary Lipids Modulate Ca2+-Dependent Mitochondrial Function in the Post-Ischemic Heart

  • Salvatore Pepe
Part of the Progress in Experimental Cardiology book series (PREC, volume 9)


A key feature of advanced age is a reduced threshold for excess Ca2+ loading during events that stimulate increased Ca2+ entry, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Remodeling of myocardial cell membranes is a major factor underlying the relative Ca2+ intolerance in senescence and greater vulnerability to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca2+ homeostasis. Age-associated membrane changes, that may also be influenced by diet, include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA, cardiolipin. These alterations have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3: omega-6 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.

Key words

omega-3 polyunsaturated fatty acids cardiolipin mitochondria calcium 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hansford R. 1983. Bioenergetics in aging. Biochim Biophys Acta 726:41–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, Capasso JM. 1990. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res 67:871–885.PubMedCrossRefGoogle Scholar
  3. 3.
    Olivetti G, Melissari M, Capasso JM, Anversa P. 1991. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68:1560–1568.PubMedCrossRefGoogle Scholar
  4. 4.
    Walker K, Lakatta E, Houser S. 1993. Age-associated changes in membrane currents in rat ventriculuar myocytes. Cardiovasc Res 27:1968–1977.PubMedCrossRefGoogle Scholar
  5. 5.
    Lakatta EG. 1992. Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart. Cardiovasc Res 26:193–214.PubMedCrossRefGoogle Scholar
  6. 6.
    Lakatta EG. 1993. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 73:413–467.PubMedGoogle Scholar
  7. 7.
    Lakatta EG. 1998. Cardiovascular aging: Perspectives from humans to rodents. Am J Geriat Cardiol 7:32–45.Google Scholar
  8. 8.
    Froehlich J, Lakatta E, Beard E, Spurgeon H, Weisfeldt M, Gerstenblith G. 1978. Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium. J Mol Cell Cardiol 10:427-438.PubMedCrossRefGoogle Scholar
  9. 9.
    Schmidt U, delMonte F, Miyamoto M, Matsui T, Gwathmey J, Rosenzweig A, Hajjar R. 1999. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase. Circulation 101:790–796.CrossRefGoogle Scholar
  10. 10.
    Narayanan N. 1981. Differential alterations in ATP-supported calcium transport activities of sarcoplasmic reticulum and sarcolemma of aging myocardium. Biochim Biophys Acta 678:442–459.PubMedCrossRefGoogle Scholar
  11. 11.
    Heyliger C, Prakash A, McNeill J. 1988. Alterations in membrane Na+−Ca2+ exchange in the aging myocardium. Age 11:1–6.CrossRefGoogle Scholar
  12. 12.
    Heyliger C, Prakash A, McNeill J. 1989. Effect of calmodulin on sarcoplasmic reticular Ca2+ transport in the aging heart. Mol Cell Biochem 85:75–79.PubMedCrossRefGoogle Scholar
  13. 13.
    Josephson R, Silverman H, Lakatta E, Stern M, Zweier J. 1991. Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes. J Biol Chem 266:2354–2361.PubMedGoogle Scholar
  14. 14.
    Gunter TE, Pffeifer DR. 1990. Mechanisms by which mitochondria transport calcium. Am J Physiol 258:C755–C786.PubMedGoogle Scholar
  15. 15.
    Hansford R. 1994. Physiological role of mitochondrial calcium transport. J Bioenerg Biomemb 26:495–508.CrossRefGoogle Scholar
  16. 16.
    Hano O, Bogdanov K, Sakai M, Danziger R, Spurgeon H, Lakatta E. 1995. Reduced threshold for myocardial cell calcium intolerance in the rat heart with aging. Am J Physiol 269:H1607–H1612.PubMedGoogle Scholar
  17. 17.
    Miyata H, Lakatta E, Stern M, Silverman H. 1992. Relation of mitochondrial and cytosolic free calcium to cardiac myocyte recovery after exposure to anoxia. Circ Res 71:605–613.PubMedCrossRefGoogle Scholar
  18. 18.
    Miyata H, Silverman H, Sollott S, Lakatta E, Stern M, Hansford R. 1991. Measurement of mitochondrial free Ca2+ concentration in living single rat cardiac myocytes. Am J Physiol 261:H1123–H1134.PubMedGoogle Scholar
  19. 19.
    Ferrari R. 1996. The role of mitochondria in ischemic heart disease. J Cardiovasc Pharmacol 28(supplement 1):S1–S10.PubMedGoogle Scholar
  20. 20.
    DiLisa F, Menabo R, Canton M, Petronilli V. 1998. The role of mitochondria in the salvage and injury of the ischemic myocardium. Biochim Biophys Acta 1366:69–78.CrossRefGoogle Scholar
  21. 21.
    Halestrap A, Kerr P, Javador S, Woodfield K. 1998. Elucidationg the mechanism of the permeability transition pore and its role in reperfusion injury in the heart. Biochim Biophys Acta 1366:79–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Pepe S, Tsuchiya N, Lakatta E, Hansford R. 1999. PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. Am J Physiol 276:H149–H158.PubMedGoogle Scholar
  23. 23.
    Jahangir A, Ozean C, Holmuhamedov EL, Terzic A. 2001. Increased calcium vulnerability of senescent cardiac mitochondria: protective role for a mitochondrial potassium channel opener. Mech Ageing Dev 122:1073–1086.PubMedCrossRefGoogle Scholar
  24. 24.
    Nohl H, Breuninger V, Hegner D. 1978. Influence of mitochondrial radical formation on energy linked respiration. Eur J Biochem 90:385–390.PubMedCrossRefGoogle Scholar
  25. 25.
    Sawada M, Carlson J. 1987. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech Aging Dev 41:125–137.PubMedCrossRefGoogle Scholar
  26. 26.
    Sohal R, Arnold L, Sohal B. 1990. Age-related changes in antioxidant enzymes and prooxidant generation in tissues of the rat with special reference to parameters in two insect species. Free Rad Biol Med 10:495–500.CrossRefGoogle Scholar
  27. 27.
    Papa S. 1996. Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochim Biophys Acta 1276:87–105.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosenfeldt FL, Pepe S, Ou R, Mariani JA, Rowland MA, Nagley P, Linanne AW. 1999. Coenzyme Q10 improves the tolerance of senescent myocardium to aerobic and ischemic stress: studies in rats and human atrial tissue. Biofactors 9:291–299.PubMedCrossRefGoogle Scholar
  29. 29.
    Ambrosio G, Zweier J, Duilio C, Kuppusamy P, Santoro G, Elia P, Tritto I, Cirillo P. 1993. Evidence that mitochondrial respiration is a source of potentially toxic oxygen free readicals in intact rabbit hearts subjected to ischemia and reflow. J Biol Chem 268:18532–18541.PubMedGoogle Scholar
  30. 30.
    McCord JM. 1985. Oxygen derived free radicals in post ischemic tissue injury. New Engl J Med 312:159–163.PubMedCrossRefGoogle Scholar
  31. 31.
    Esterbauer H, Schaur R, Zollner H. 1991. Chemistry and biochemistry of 4-hydroxynonenal, mal-onaldehyde and related aldehydes. Free Rad Biol Med 11:81–128.PubMedCrossRefGoogle Scholar
  32. 32.
    Lapidus RG, Sokolov PM. 1994. The mitochondrial permeability transition. Interactions of spermine, ADP and inorganic phosphate. J Biol Chem 269:18931–18936.PubMedGoogle Scholar
  33. 33.
    Lenaz G. 1998. Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta 1366:53–68.PubMedCrossRefGoogle Scholar
  34. 34.
    Lucas D, Szweda L. 1998. Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction. Proc Natl Acad Sei U.S.A. 95:510–514.CrossRefGoogle Scholar
  35. 35.
    Lucas D, Szweda L. 1999. Declines in mitochondrial respiration during cardiac reperfusion: age-dependent inactivation of α-ketoglutarate dehydrogenase. Proc Natl Acad Sei, U.S.A. 96:6689–6693.CrossRefGoogle Scholar
  36. 36.
    Blasig I, Grune T, Schonheit K, Rohde E, Jakstadt M, Haseloff R, Siems W. 1995. 4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion. Am J Physiol 268:H14–H22.Google Scholar
  37. 37.
    Das D, George A, Liu X, Rao P. 1989. Detection of the hydroxyl radical in the mitochondria of ischemic-reperfused myocardium by trapping salicylate. Biochem Biophys Res Commun 165:1004–1009.PubMedCrossRefGoogle Scholar
  38. 38.
    Humphries K, Szweda L. 1998. Selective inactivation of α-ketoglutarate dehydrogenase and pyruvate dehydrogenase: reaction of lipoic acid with 4-hydroxy-2-nonenal. Biochemistry (USA) 37:15835–15841.CrossRefGoogle Scholar
  39. 39.
    Humphries K, Yoo Y, Szweda L. 1998. Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal. Biochemistry (USA) 37:552–557.CrossRefGoogle Scholar
  40. 40.
    Phillipson R, Ward R. 1985. Effects of fatty acids on Na2+/Ca2+ exchange and calcium permeability of cardiac sarcoplasmic reticulum vesicles. J Biol Chem 260:9666–9671.Google Scholar
  41. 41.
    Swanson J, Likesh B, Kinsella J. 1989. Ca2+/Mg2+ATPase of mouse cardiac sarcoplasmic reticulum is affected by membrane n-6 and n-3 polyunsaturated fatty acid content. J Nutr 119:364–372.PubMedGoogle Scholar
  42. 42.
    Taffet G, Pharm T, Bick D, Entma M, Pownall H, Bick R. 1993. The calcium uptake of the rat heart sarcoplasmic reticulum is altered by dietary lipid. J Memb Biol 131:35–42.CrossRefGoogle Scholar
  43. 43.
    Billman G, Hallaq H, Leaf A. 1994. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Nat Acad Sei U.S.A. 91:4427–4430.CrossRefGoogle Scholar
  44. 44.
    Hallaq H, Smith T, Leaf A. 1992. Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids. Proc Nat Acad Sei USA 89:1760–1764.CrossRefGoogle Scholar
  45. 45.
    Pepe S, Bogdanov K, Hallaq H, Spurgeon H, Leaf A, Lakatta E. 1994. ω-3 Polyunsaturated fatty acid modulates dihydropyridine effects on L-type Ca2+ channels, cytosolic Ca2+, and contraction in adult rat cardiac myocytes. Proc Nat Acad Sei U.S.A. 91:8832–8836.CrossRefGoogle Scholar
  46. 46.
    Bogdanov K, Spurgeon H, Vinogradova T, Lakatta E. 1998. Modulation of the transient outward current in adult rat ventricular myocytes by polyunsaturated fatty acids. Am J Physiol 274: H571–H579.PubMedGoogle Scholar
  47. 47.
    Xiao YF, Kang JX, Morgan JP, Leaf A. 1995. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci USA 21;92:11000–11004.Google Scholar
  48. 48.
    Xiao YF, Gomez AM, Morgan JP, Lederer WJ, Leaf A. 1997. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci USA 94:4182–4187.PubMedCrossRefGoogle Scholar
  49. 49.
    Pepe S, McLennan P. 2002. Increased ventricular fibrillation threshold and reduced incidence of cardiac arrhythmias after polyunsaturated fish oil dietary supplementation. Circulation 105:2303–2308.PubMedCrossRefGoogle Scholar
  50. 50.
    Demaison L, Sergiel JP, Moreau D, Grynberg A. 1994. Influence of the phospholipid n-3/n-6 PUFA ratio on mitochondrial oxidative metabolism before and after myocardial ischemia. Biochim Biophys Acta 1227:53–59.PubMedCrossRefGoogle Scholar
  51. 51.
    Pepe S, McLennan P. 1996. Increased ventricular fibrillation threshold and reduced incidence of cardiac arrhythmias after polyunsaturated fish oil dietary supplementation. J Nutr 126:34–42.PubMedGoogle Scholar
  52. 52.
    McLennan P, Abeywardena M, Charnock J. 1990. Reversal of the arrhythmogenic effects of long-term saturated fatty acid intake by dietary n-3 and n-6 polyunsaturated fatty acids. Am J Clin Nutr 51:53–58.PubMedGoogle Scholar
  53. 53.
    McLennan P, Abeywardena M, Charnock J. 1989. The influence of age and dietary fat in animal model of sudden cardiac death. Aus NZ J Med 19:1–5.CrossRefGoogle Scholar
  54. 54.
    Beyer K, Klingenberg M. 1985. ADP/ATP carrier protein from beef heart mitochondria has high amounts of tightly bound cardiolipin, as revealed by 31P nuclear magnetic resonance. Biochemistry 24:3821–3826.PubMedCrossRefGoogle Scholar
  55. 55.
    Noel H, Pande SV. 1986. An essential requirement of cardiolipin for mitochondrial acetylcarnitine translocase activity. Eur J Biochem 155:99–102.PubMedCrossRefGoogle Scholar
  56. 56.
    Paradies G, Petrosillo G, Pistolese M, Ruggiero F. 2000. The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Letters 466:323–326.PubMedCrossRefGoogle Scholar
  57. 57.
    Matlib MA, Zhou Z, Knight S, Ahmed S, Choi KM, Krause-Bauer J, Phillips R, Altschuld R, Katsube Y, Sperelakis N, Bers DM. 1998. Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes. J Biol Chem 273:10223–10231.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  1. 1.Cardiac Surgical Research Unit, Baker Heart Research InstituteMonash University Faculty of MedicineMelbourneAustralia

Personalised recommendations