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Alcohol-Induced Mitochondrial Changes in the Liver

  • Ellen R. Gordon

Abstract

The chronic ingestion of ethanol results in liver-cell damage, and characteristic features of this injury are the marked alterations in both the functions and morphology of the mitochondria. Morphologically, the changes observed in human alcoholics and experimental animals appear similar. Bizarrely shaped mitochondria and megamitochondria are detected at the fatty liver stage and persist as the disease progresses. As yet, however, no correlation has been found between the severity of these morphological changes and the development of cirrhosis. Analysis of the mitochondrial membranes indicates that ethanol consumption produces changes in both the protein and lipid composition of the membrane. Profound decreases in the components of the respiratory chain have been detected, and these changes are associated with marked depressions in the activity of NAD+-linked dehydrogenases, cytochrome oxidase, and the ATP synthetase complex. On the other hand, no consistent pattern has emerged as to the effect of chronic ethanol consumption on the composition of the membrane phospholipids. Many of the changes appear to be dependent on the sex of the animal, the dietary status, and the duration of ethanol intake, and are suggestive of changes in fatty acid desaturase activity. Mitochondria isolated from ethanol-fed rats displayed impaired respiration and a lowered steady-state rate of ATP synthesis. Whether or not these functional changes are directly related to alterations in the physical properties of the membranes remains to be resolved. This marked depression of respiratory functions in isolated mitochondria was not reflected by a significant decrease in O2 consumption by the livers of ethanol-fed animals.

Keywords

Liver Mitochondrion Aldehyde Dehydrogenase Alcoholic Liver Disease Chronic Ethanol Mitochondrial Protein Synthesis 
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.

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References

  1. 1.
    French SW: Succinic dehydrogenase: Histochemical “shift” in hepatic lobular distribution induced by ethanol. Lab Invest 13:1051–1056, 1964.PubMedGoogle Scholar
  2. 2.
    Porta EA, Koch OR, Hartcroft WS: A new experimental approach in the study of chronic alcoholism. IV. Reproduction of alcoholic cirrhosis in rats and the role of lipotropes versus vitamins. Lab Invest 20:562–572, 1969.PubMedGoogle Scholar
  3. 3.
    French SW, Todoroff T: Hepatic mitochondrial fragility and permeability. Arch Pathol 89:329–336, 1970.PubMedGoogle Scholar
  4. 4.
    Rubin E, Beattie DS, Toth A, et al: Structural and functional effects of ethanol in hepatic mitochondria. Fed Proc. Fed Am Soc Exp Biol 31:131–140, 1972.Google Scholar
  5. 5.
    Rubin E, Lieber CS: Fatty liver, alcoholic hepatitis and cirrhosis produced by alcohol in primates. N Engl J Med 290:128–135, 1974.PubMedCrossRefGoogle Scholar
  6. 6.
    Koch OR, Roatta LL, Bolanos LP, et al: Ultrastructural and biochemical aspects in liver mitochondria during recovery from ethanol-induced alterations. Am J Pathol 90:325–344, 1978.PubMedGoogle Scholar
  7. 7.
    Kiessling K, Pilstrom L, Strundberg B, et al: Ethanol and the human liver: Correlation between mitochondrial size and degree of ethanol abuse. Acta Med Scand 178:533–538, 1965.CrossRefGoogle Scholar
  8. 8.
    Rubin E, Lieber CS: Early fine structural changes in the human liver induced by alcohol. Gastroenterology 52:1–13, 1967.PubMedGoogle Scholar
  9. 9.
    Bruguera M, Bertman A, Bombi JA, et al: Giant mitochondria in hepatocytes: A diagnostic hint for alcoholic liver disease. Gastroenterology 73:1383–1387, 1977.PubMedGoogle Scholar
  10. 10.
    Patek AJ Jr: Alcohol, nutrition and alcoholic cirrhosis. Am J Clin Nutr 32:1304–1312, 1979.PubMedGoogle Scholar
  11. 11.
    Geokas MC, Lieber CS, French SW, et al: Ethanol, the liver and the gastrointestinal tract. Ann Intern Med 95:198–211, 1981.PubMedGoogle Scholar
  12. 12.
    Jenkins WJ, Peters TJ: Mitochondrial enzyme activities in liver biopsies from patients with alcoholic liver disease. Gut 19:341–344, 1978.PubMedCrossRefGoogle Scholar
  13. 13.
    French SW, Ruebner BH, Mezey F, et al: Effect of chronic ethanol feeding on hepatic mitochondria in the monkey. Hepatology 3:34–40, 1983.PubMedCrossRefGoogle Scholar
  14. 14.
    Trump BD, Ericson JLE: Some ultrastructural and biochemical consequences of cell injury, in Zwerfark BW, Grant L, McCluskey RT (eds): The Inflammatory Process. New York, Academic Press, 1965, pp. 35–120.Google Scholar
  15. 15.
    Gordon ER, Lough J: Ultrastructural and biochemical aspects during the regression of an ethanol induced fatty liver. Lab Invest 26:154–162, 1972.PubMedGoogle Scholar
  16. 16.
    French SW: Fragility of liver mitochondria in ethanol-fed rats. Gastroenterology 54:1106–1110, 1963.Google Scholar
  17. 17.
    Rouiller C: Experimental toxic injury of the liver, in Rouiller C. (ed): The Liver. New York, Academic Press, 1964, pp. 355–476.Google Scholar
  18. 18.
    Kujawa M, Karwacka H: Ultrastructural and biochemical studies of the brain and other organs in rats after chronic ethanol administration. IV. Stereological analysis of mitochondria from rat liver cells after intoxication with various ethanol doses. Exp Pathol (Jena) 18:329–335,1980.Google Scholar
  19. 19.
    Kiessling KH, Blander K: Biochemical changes in rat tissue after prolonged alcohol consumption. Q J Stud Alcohol 22:535–538, 1961.Google Scholar
  20. 20.
    French SW, Ihrig TJ, Morin RJ: Lipid composition of R.B.C. ghosts, liver mitochondria and microsomes of ethanol-fed rats. Q J Stud Alcohol 31:801–809, 1980.Google Scholar
  21. 21.
    French SW, Ihrig TJ, Shaw GP, et al: The effect of ethanol on the fatty acid composition of hepatic microsomes and inner and outer mitochondrial membranes. Res Commun Chem Pathol Pharmacol 2:567–585, 1971.PubMedGoogle Scholar
  22. 22.
    Thompson JA, Reitz R: Effects of ethanol ingestion and dietary fat levels on mitochondrial lipids in male and female rats. Lipids 13:540–541, 1978.PubMedCrossRefGoogle Scholar
  23. 23.
    Spach P, Parce JW, Cunningham C: Effect of chronic ethanol administration on energy metabolism and phospholipase A2 activity in rat liver. Biochem J 78:23–33, 1979.Google Scholar
  24. 24.
    Cunningham CC, Sinthusek G, Spach PI, et al: Effect of dietary ethanol and cholesterol on phospholipid composition of hepatic mitochondria and microsomes from monkey (Macaca nemestrina). Alcoholism: Clin Exp Res 5:417–426, 1981.CrossRefGoogle Scholar
  25. 25.
    Cunningham CC, Sinthusek G, Spach PI, et al: Effects of dietary ethanol and cholesterol on metabolic functions of hepatic mitochondria and microsomes from the monkey Macaca nemestrina. Alcoholism: Clin Exp Res 5:410–416, 1981.CrossRefGoogle Scholar
  26. 26.
    Arai M, Gordon ER, Lieber CS: Decreased hepatic mitochondrial cytochrome oxidase activity in ethanol-fed baboons: The possible role of phospholipid. Fed Proc Fed Am Soc Exp Biol 41:922, 1982 (abstract).Google Scholar
  27. 27.
    Schilling RJ, Reitz RC: A mechanism for ethanol-induced damage to the liver mitochondrial structure and function. Biochim Biophys Acta 603:266–277, 1980.PubMedCrossRefGoogle Scholar
  28. 28.
    Cunningham CC, Filus S, Bottenus RE, et al: Effect of ethanol consumption on the phospholipid composition of rat liver microsomes and mitochondria. Biochim Biophys Acta 712:225–233, 1982.PubMedGoogle Scholar
  29. 29.
    Waring AJ, Rottenberg H, Ohnishi T, et al: Membranes and phospholipids of liver mitochondria from chronic alcoholic rats are resistant to the membrane disordering by alcohol. Proc Natl Acad Sci USA 78:2582–2586, 1981.PubMedCrossRefGoogle Scholar
  30. 30.
    Brenner RR: The oxidative desaturation of unsaturated fatty acids in animals. Mol Cell Biochem 3:41–56, 1974.PubMedCrossRefGoogle Scholar
  31. 31.
    Nervi AM, Peluffo RD, Brenner RR, et al: Effect of ethanol administration on fatty acid desaturation. Lipids 15:263–268, 1980.PubMedCrossRefGoogle Scholar
  32. 32.
    Reitz RC, Wang L, Schilling RJ, et al: Effects of ethanol ingestion on the unsaturated fatty acids from various tissues. Prog Lipid Res 20:209–213, 1981.PubMedCrossRefGoogle Scholar
  33. 33.
    Shaw S, Jayatilleke E, Ross WA, et al: Ethanol-induced lipid peroxidation: Potentiation by long-term alcohol feeding and attenuation by methionine. J Lab Clin Med 98:417–424, 1981.PubMedGoogle Scholar
  34. 34.
    Thompson JA, Reitz RC: A possible mechanism for the increased oxidation of choline after chronic ethanol ingestion. Biochim Biophys Acta 545:381–397, 1979.PubMedCrossRefGoogle Scholar
  35. 35.
    Dreiling CE, Schilling RJ, Reitz RC: Effects of chronic ethanol ingestion in the activity of rat liver mitochondrial 2’3’ cyclic nucleotide 3-phosphohydrolase. Biochim Biophys Acta 640:121–130, 1981.PubMedCrossRefGoogle Scholar
  36. 36.
    Burke JP, Rubin E: The effects of ethanol and acetaldehyde on the products of protein synthesis by liver mitochondria. Lab Invest 41:393–400, 1979.PubMedGoogle Scholar
  37. 37.
    Bernstein JD, Penniall R: Effects of chronic ethanol treatment on rat liver mitochondrial protein synthesis. Alcoholism 2:301–310, 1978.PubMedGoogle Scholar
  38. 38.
    Arai M, Gordon E, Lieber CS: Mitochondrial functions in baboons fed ethanol chronically. Fed Proc Fed Am Soc Exp Biol 40:801, 1981 (abstract).Google Scholar
  39. 39.
    Hosein EA, Lee H, Hofrnan I: The influence of chronic ethanol feeding to rats on liver mitochondrial structure and function. Can J Biochem 58:1147–1155, 1980.PubMedCrossRefGoogle Scholar
  40. 40.
    Cederbaum AI, Lieber CS, Rubin E: Effects of chronic ethanol treatment on mitochondrial functions: Damage to coupling site 1. Arch Biochem Biophys 165:560–569, 1974.PubMedCrossRefGoogle Scholar
  41. 41.
    Thayer WS, Rubin E: Effect of chronic ethanol intoxication on oxidative phosphorylation in rat liver submitochondrial particles. J Biol Chem 254:7717–7727, 1979.PubMedGoogle Scholar
  42. 42.
    Rottenberg H, Robertson DE, Rubin E: The temperature dependence of repiration and ATPase in rat liver mitochondria is altered by ethanol. Adv Exp Med Biol 132:345–353, 1980.PubMedGoogle Scholar
  43. 43.
    Gordon ER: Mitochondrial functions in an ethanol-induced fatty liver. J Biol Chem 248:8271–8280, 1973.PubMedGoogle Scholar
  44. 44.
    Koch OR, Bedette CD, Gamboni M, et al: Functional alterations of liver mitochondria in chronic experimental alcoholism. Exp Mol Pathol 25:253–262, 1976.PubMedCrossRefGoogle Scholar
  45. 45.
    Wahid S, Khanna JM, Carmichael FJ, et al: Mitochondrial functions following chronic ethanol treatment: Effect of diet. Res Commun Chem Pathol Pharmacol 30:477–491, 1980.PubMedGoogle Scholar
  46. 46.
    Thayer WS, Rubin E: Molecular alterations in the respiratory chain of rat liver after chronic ethanol consumption. J Biol Chem 256:6090–6097, 1981.PubMedGoogle Scholar
  47. 47.
    Thayer W, Rubin E: Antimycin inhibitor as a probe of mitochondrial functions in isolated rat hepatocytes: Effects of chronic ethanol consumption. Biochim Biophys Acta 721:328–335, 1982.PubMedCrossRefGoogle Scholar
  48. 48.
    Thayer WS, Ohnishi T, Rubin E: Characterization of iron sulfur clusters in rat liver submitochondrial particles by electron paramagnetic resonance spectroscopy alterations produced by chronic ethanol consumption. Biochim Biophys Acta 591:22–36, 1980.PubMedCrossRefGoogle Scholar
  49. 49.
    Bottenus RE, Spach PI, Filus S, et al: Effect of chronic ethanol consumption on energy-linked processes associated with oxidative phosphorylation: Protein translocation and ATP-Pi exchange. Biochim Biophys Res Commun 105:1368–1373, 1982.CrossRefGoogle Scholar
  50. 50.
    Weiner H: Acetaldehyde metabolism, in Majchrowicz E, Noble EP (eds): Biochemistry and Pharmacology of Ethanol, New York and London, Plenum Press, vol I. 1979, pp. 125–142.Google Scholar
  51. 51.
    Lindros KO: Acetaldehyde oxidation and the role in the overall metabolic effects of ethanol in the liver, in Lundquist F, Tygstrup N (eds): Regulation of Hepatic Metabolism. New York, Academic Press, 1974, pp 417–443.Google Scholar
  52. 52.
    Parrilla R, Ohkawa K, Kindros KO, et al: Functional compartmentation of acetaldehyde oxidation in rat liver. J Biol Chem 249:4926–4933, 1974.PubMedGoogle Scholar
  53. 53.
    Tottmar SOC, Pettersson H, Kiessling KH: The subcellular distribution and properties of aldehyde dehydrogenase in rat liver. Biochem J 135:577–586, 1973.PubMedGoogle Scholar
  54. 54.
    Horton AA, Barrett MC: The subcellular localization of aldehyde dehydrogenase in rat liver. Arch Biochem Biophys 167:426–436, 1975.PubMedCrossRefGoogle Scholar
  55. 55.
    Hasumura Y, Teschke R, Lieber CS: Characteristics of acetaldehyde oxidation in rat liver mitochondria. J Biol Chem 254:4908–4913, 1976.Google Scholar
  56. 56.
    Lebsack ME, Gordon ER, Lieber CS: Effect of chronic ethanol consumption on aldehyde dehydrogenase activity in the baboon. Biochem Pharmacol 30:2273–2277, 1981.PubMedCrossRefGoogle Scholar
  57. 57.
    Kraemer RJ, Deitrich RA: Isolation and characterization of human aldehyde dehydrogenase. J Biol Chem 243:6402–6408, 1968.PubMedGoogle Scholar
  58. 58.
    Blair AH, Boley FH: Human liver aldehyde dehydrogenase: Partial purification and properties. Can J Biochem 47:265–272, 1969.PubMedGoogle Scholar
  59. 59.
    Greenfield NJ, Pietrusyko R: Two aldehyde dehydrogenases from human liver: Isolation via affinity chromatography and characterization of the isoenzymes. Biochim Biophys Acta 483:35–45, 1977.PubMedGoogle Scholar
  60. 60.
    Harada S, Agarwal DP, Goedde HW: Electrophoretic and biochemical studies of human aldehyde dehydrogenase: Isoenzymes in various tissues. Life Sci 26:1773–1780, 1980.PubMedCrossRefGoogle Scholar
  61. 61.
    Koivula T: Subcellular distribution and characterization of human aldehyde dehydrogenase. Life Sci 16:1563–1570, 1975.PubMedCrossRefGoogle Scholar
  62. 62.
    Alderman J, Sanny CG, Gordon ER, et al: Partial characterization of hepatic aldehyde dehydrogenase from the baboon, in Weiner H, Wermuth W (eds): Enzymology of Carbonyl Metabolism: Aldehyde Dehydrogenases and Aldo/Keto Reductase. New York, Alan Liss, 1982, pp. 77–89.Google Scholar
  63. 63.
    Bennett AF, Buckley PD, Blackwell LF: Inhibitors of dehydrogenase activity of sheep liver cytoplasmic aldehyde dehydrogenase. Biochemistry 22:776–784, 1983.PubMedCrossRefGoogle Scholar
  64. 64.
    Takahashi K, Weiner H: Magnesium stimulation of catalytic activity of horse liver aldehyde dehydrogenase: Changes in molecular weight and catalytic sites. J Biol. Chem 255:8206–8209, 1980.PubMedGoogle Scholar
  65. 65.
    Jenkins WJ, Peters TJ: Subcellular distribution and properties of aldehyde dehydrogenase in human liver. Clin Sci Mol Med 55:11, 1978.Google Scholar
  66. 66.
    Lieber CS, DeCarli LM: The role of the hepatic microsomal ethanol oxidizing systems (MEOS) in ethanol metabolism in vivo. J. Pharmacol Exp Ther 181:279–287, 1972.Google Scholar
  67. 67.
    Orrego H, Israel Y, Blendis LM: Alcoholic liver disease: Information in search of knowledge. Hepatology 1:267:283, 1981.Google Scholar
  68. 68.
    Rubin E, Rottenberg H: Ethanol-induced injury and adaptation in biological membranes. Fed Proc Fed Am Soc Exp Biol 41:2465–2471, 1982.Google Scholar
  69. 69.
    Gordon ER, Rochman J, Arai M, et al: Lack of correlation betwen hepatic mitochondrial membrane structure and function in ethanol-fed rats. Science 216:1319–1321, 1982.PubMedCrossRefGoogle Scholar
  70. 70.
    Williams MA, Stancliff RC, Packer L, et al: Relation of unsaturated fatty acid composition of rat liver mitochondria to oscillation period, spin label motion, permeability and oxidative phosphorylation. Biochim Biophys Acta 267:444–456, 1972.PubMedCrossRefGoogle Scholar
  71. 71.
    Tygstrup N, Winkler K, Lundquist F: The mechanism of the fructose effect on the ethanol metabolism of the human liver. J Clin Invest 44:817–830, 1965.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Ellen R. Gordon
    • 1
  1. 1.Yale Liver Study UnitYale University School of MedicineNew HavenUSA

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