Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Nov 1;367(Pt 3):889–894. doi: 10.1042/BJ20020625

Mitochondrial oxidative stress is modulated by oleic acid via an epidermal growth factor receptor-dependent activation of glutathione peroxidase.

Carine Duval 1, Nathalie Augé 1, Marie-Françoise Frisach 1, Louis Casteilla 1, Robert Salvayre 1, Anne Nègre-Salvayre 1
PMCID: PMC1222939  PMID: 12153397

Abstract

Mitochondria generate reactive oxygen species (ROS) under various pathophysiological conditions. In isolated mitochondria, fatty acids (FA) exhibit an uncoupling effect of the respiratory activity and modulate ROS generation. The effect of FA on intact cultured cells remains to be elucidated. The present study reports that FA (buffered by BSA) decrease the level of cellular ROS generated by the mitochondrial respiratory chain in cultured cells incubated with antimycin A. Both saturated and unsaturated FA are effective. This fatty acid-induced antioxidant effect does not result from a decrease in ROS production, but is subsequent to cellular glutathione peroxidase (GPx) activation and enhanced ROS degradation. This fatty acid-induced GPx activation is mediated through epidermal growth factor receptor (EGFR) signalling, since this response is (i) abrogated by the EGFR inhibitor AG1478 or by a defect in EGFR (in EGFR-deficient B82L fibroblasts), (ii) restored in B82LK+ cells expressing EGFR and (iii) mimicked by epidermal growth factor. These findings indicate that FA contribute to enhance cellular antioxidant defences against mitochondrial oxidative stress through EGFR-dependent GPx activation.

Full Text

The Full Text of this article is available as a PDF (159.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albers D. S., Beal M. F. Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl. 2000;59:133–154. doi: 10.1007/978-3-7091-6781-6_16. [DOI] [PubMed] [Google Scholar]
  2. Arthur J. R. The glutathione peroxidases. Cell Mol Life Sci. 2000 Dec;57(13-14):1825–1835. doi: 10.1007/PL00000664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asayama K., Nakane T., Dobashi K., Kodera K., Hayashibe H., Uchida N., Nakazawa S. Effect of obesity and troglitazone on expression of two glutathione peroxidases: cellular and extracellular types in serum, kidney and adipose tissue. Free Radic Res. 2001 Apr;34(4):337–347. doi: 10.1080/10715760100300291. [DOI] [PubMed] [Google Scholar]
  4. Aspberg A., Tottmar O. Oxidative stress decreases antioxidant enzyme activities in reaggregation cultures of rat brain cells. Free Radic Biol Med. 1994 Dec;17(6):511–516. doi: 10.1016/0891-5849(94)90090-6. [DOI] [PubMed] [Google Scholar]
  5. Bae Y. S., Kang S. W., Seo M. S., Baines I. C., Tekle E., Chock P. B., Rhee S. G. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem. 1997 Jan 3;272(1):217–221. [PubMed] [Google Scholar]
  6. Bandyopadhyay G. K., Hwang S., Imagawa W., Nandi S. Role of polyunsaturated fatty acids as signal transducers: amplification of signals from growth factor receptors by fatty acids in mammary epithelial cells. Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):71–78. doi: 10.1016/0952-3278(93)90012-l. [DOI] [PubMed] [Google Scholar]
  7. Boveris A., Cadenas E., Stoppani A. O. Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem J. 1976 May 15;156(2):435–444. doi: 10.1042/bj1560435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Boveris A., Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J. 1973 Jul;134(3):707–716. doi: 10.1042/bj1340707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Boveris A., Oshino N., Chance B. The cellular production of hydrogen peroxide. Biochem J. 1972 Jul;128(3):617–630. doi: 10.1042/bj1280617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brigelius-Flohé R. Tissue-specific functions of individual glutathione peroxidases. Free Radic Biol Med. 1999 Nov;27(9-10):951–965. doi: 10.1016/s0891-5849(99)00173-2. [DOI] [PubMed] [Google Scholar]
  11. Cadenas E., Boveris A. Enhancement of hydrogen peroxide formation by protophores and ionophores in antimycin-supplemented mitochondria. Biochem J. 1980 Apr 15;188(1):31–37. doi: 10.1042/bj1880031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chance B., Sies H., Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 1979 Jul;59(3):527–605. doi: 10.1152/physrev.1979.59.3.527. [DOI] [PubMed] [Google Scholar]
  13. Chandrasekar B., Colston J. T., Freeman G. L. Induction of proinflammatory cytokine and antioxidant enzyme gene expression following brief myocardial ischaemia. Clin Exp Immunol. 1997 May;108(2):346–351. doi: 10.1046/j.1365-2249.1997.d01-1017.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chowdhury S. K., Drahota Z., Floryk D., Calda P., Houstek J. Activities of mitochondrial oxidative phosphorylation enzymes in cultured amniocytes. Clin Chim Acta. 2000 Aug;298(1-2):157–173. doi: 10.1016/s0009-8981(00)00300-4. [DOI] [PubMed] [Google Scholar]
  15. Cocco T., Di Paola M., Papa S., Lorusso M. Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Free Radic Biol Med. 1999 Jul;27(1-2):51–59. doi: 10.1016/s0891-5849(99)00034-9. [DOI] [PubMed] [Google Scholar]
  16. Csonka C., Pataki T., Kovacs P., Müller S. L., Schroeter M. L., Tosaki A., Blasig I. E. Effects of oxidative stress on the expression of antioxidative defense enzymes in spontaneously hypertensive rat hearts. Free Radic Biol Med. 2000 Oct 1;29(7):612–619. doi: 10.1016/s0891-5849(00)00365-8. [DOI] [PubMed] [Google Scholar]
  17. Dulin N. O., Sorokin A., Douglas J. G. Arachidonate-induced tyrosine phosphorylation of epidermal growth factor receptor and Shc-Grb2-Sos association. Hypertension. 1998 Dec;32(6):1089–1093. doi: 10.1161/01.hyp.32.6.1089. [DOI] [PubMed] [Google Scholar]
  18. Gamou S., Shimizu N. Hydrogen peroxide preferentially enhances the tyrosine phosphorylation of epidermal growth factor receptor. FEBS Lett. 1995 Jan 3;357(2):161–164. doi: 10.1016/0014-5793(94)01335-x. [DOI] [PubMed] [Google Scholar]
  19. Goss J. R., Taffe K. M., Kochanek P. M., DeKosky S. T. The antioxidant enzymes glutathione peroxidase and catalase increase following traumatic brain injury in the rat. Exp Neurol. 1997 Jul;146(1):291–294. doi: 10.1006/exnr.1997.6515. [DOI] [PubMed] [Google Scholar]
  20. Hardy S., Langelier Y., Prentki M. Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects. Cancer Res. 2000 Nov 15;60(22):6353–6358. [PubMed] [Google Scholar]
  21. Hassinen I., Ito K., Nioka S., Chance B. Mechanism of fatty acid effect on myocardial oxygen consumption. A phosphorus NMR study. Biochim Biophys Acta. 1990 Aug 9;1019(1):73–80. doi: 10.1016/0005-2728(90)90126-o. [DOI] [PubMed] [Google Scholar]
  22. Hensley K., Robinson K. A., Gabbita S. P., Salsman S., Floyd R. A. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med. 2000 May 15;28(10):1456–1462. doi: 10.1016/s0891-5849(00)00252-5. [DOI] [PubMed] [Google Scholar]
  23. Hermesh O., Kalderon B., Bar-Tana J. Mitochondria uncoupling by a long chain fatty acyl analogue. J Biol Chem. 1998 Feb 13;273(7):3937–3942. doi: 10.1074/jbc.273.7.3937. [DOI] [PubMed] [Google Scholar]
  24. Inoguchi T., Li P., Umeda F., Yu H. Y., Kakimoto M., Imamura M., Aoki T., Etoh T., Hashimoto T., Naruse M. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000 Nov;49(11):1939–1945. doi: 10.2337/diabetes.49.11.1939. [DOI] [PubMed] [Google Scholar]
  25. Khan W. A., Blobe G. C., Hannun Y. A. Arachidonic acid and free fatty acids as second messengers and the role of protein kinase C. Cell Signal. 1995 Mar;7(3):171–184. doi: 10.1016/0898-6568(94)00089-t. [DOI] [PubMed] [Google Scholar]
  26. Kondoh M., Inoue Y., Atagi S., Futakawa N., Higashimoto M., Sato M. Specific induction of metallothionein synthesis by mitochondrial oxidative stress. Life Sci. 2001 Sep 21;69(18):2137–2146. doi: 10.1016/s0024-3205(01)01294-2. [DOI] [PubMed] [Google Scholar]
  27. Korshunov S. S., Korkina O. V., Ruuge E. K., Skulachev V. P., Starkov A. A. Fatty acids as natural uncouplers preventing generation of O2.- and H2O2 by mitochondria in the resting state. FEBS Lett. 1998 Sep 18;435(2-3):215–218. doi: 10.1016/s0014-5793(98)01073-4. [DOI] [PubMed] [Google Scholar]
  28. Leonarduzzi G., Arkan M. C., Başağa H., Chiarpotto E., Sevanian A., Poli G. Lipid oxidation products in cell signaling. Free Radic Biol Med. 2000 May 1;28(9):1370–1378. doi: 10.1016/s0891-5849(00)00216-1. [DOI] [PubMed] [Google Scholar]
  29. Liu S. S. Generating, partitioning, targeting and functioning of superoxide in mitochondria. Biosci Rep. 1997 Jun;17(3):259–272. doi: 10.1023/a:1027328510931. [DOI] [PubMed] [Google Scholar]
  30. Loschen G., Azzi A., Richter C., Flohé L. Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett. 1974 May 15;42(1):68–72. doi: 10.1016/0014-5793(74)80281-4. [DOI] [PubMed] [Google Scholar]
  31. Mabile L., Meilhac O., Escargueil-Blanc I., Troly M., Pieraggi M. T., Salvayre R., Nègre-Salvayre A. Mitochondrial function is involved in LDL oxidation mediated by human cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1997 Aug;17(8):1575–1582. doi: 10.1161/01.atv.17.8.1575. [DOI] [PubMed] [Google Scholar]
  32. Matés J. M., Pérez-Gómez C., Núez de Castro I. Antioxidant enzymes and human diseases. Clin Biochem. 1999 Nov;32(8):595–603. doi: 10.1016/s0009-9120(99)00075-2. [DOI] [PubMed] [Google Scholar]
  33. Nobes C. D., Hay W. W., Jr, Brand M. D. The mechanism of stimulation of respiration by fatty acids in isolated hepatocytes. J Biol Chem. 1990 Aug 5;265(22):12910–12915. [PubMed] [Google Scholar]
  34. Nègre-Salvayre A., Hirtz C., Carrera G., Cazenave R., Troly M., Salvayre R., Pénicaud L., Casteilla L. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 1997 Aug;11(10):809–815. [PubMed] [Google Scholar]
  35. Polla B. S., Cossarizza A. Stress proteins in inflammation. EXS. 1996;77:375–391. doi: 10.1007/978-3-0348-9088-5_25. [DOI] [PubMed] [Google Scholar]
  36. Powers S. K., Ji L. L., Leeuwenburgh C. Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Med Sci Sports Exerc. 1999 Jul;31(7):987–997. doi: 10.1097/00005768-199907000-00011. [DOI] [PubMed] [Google Scholar]
  37. Price L. T., Chen Y., Frank L. Epidermal growth factor increases antioxidant enzyme and surfactant system development during hyperoxia and protects fetal rat lungs in vitro from hyperoxic toxicity. Pediatr Res. 1993 Nov;34(5):577–585. doi: 10.1203/00006450-199311000-00005. [DOI] [PubMed] [Google Scholar]
  38. Ramakrishnan N., Kalinich J. F., McClain D. E. Ebselen inhibition of apoptosis by reduction of peroxides. Biochem Pharmacol. 1996 Jun 14;51(11):1443–1451. doi: 10.1016/0006-2952(96)00084-6. [DOI] [PubMed] [Google Scholar]
  39. Rao G. N., Baas A. S., Glasgow W. C., Eling T. E., Runge M. S., Alexander R. W. Activation of mitogen-activated protein kinases by arachidonic acid and its metabolites in vascular smooth muscle cells. J Biol Chem. 1994 Dec 23;269(51):32586–32591. [PubMed] [Google Scholar]
  40. Rigoulet M., Devin A., Avéret N., Vandais B., Guérin B. Mechanisms of inhibition and uncoupling of respiration in isolated rat liver mitochondria by the general anesthetic 2,6-diisopropylphenol. Eur J Biochem. 1996 Oct 1;241(1):280–285. doi: 10.1111/j.1432-1033.1996.0280t.x. [DOI] [PubMed] [Google Scholar]
  41. Royall J. A., Ischiropoulos H. Evaluation of 2',7'-dichlorofluorescin and dihydrorhodamine 123 as fluorescent probes for intracellular H2O2 in cultured endothelial cells. Arch Biochem Biophys. 1993 May;302(2):348–355. doi: 10.1006/abbi.1993.1222. [DOI] [PubMed] [Google Scholar]
  42. Skulachev V. P. Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta. 1998 Feb 25;1363(2):100–124. doi: 10.1016/s0005-2728(97)00091-1. [DOI] [PubMed] [Google Scholar]
  43. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  44. Spolarics Z. Endotoxin stimulates gene expression of ROS-eliminating pathways in rat hepatic endothelial and Kupffer cells. Am J Physiol. 1996 Apr;270(4 Pt 1):G660–G666. doi: 10.1152/ajpgi.1996.270.4.G660. [DOI] [PubMed] [Google Scholar]
  45. Steinbrecher U. P. Role of superoxide in endothelial-cell modification of low-density lipoproteins. Biochim Biophys Acta. 1988 Mar 4;959(1):20–30. doi: 10.1016/0005-2760(88)90145-2. [DOI] [PubMed] [Google Scholar]
  46. Suc I., Meilhac O., Lajoie-Mazenc I., Vandaele J., Jürgens G., Salvayre R., Nègre-Salvayre A. Activation of EGF receptor by oxidized LDL. FASEB J. 1998 Jun;12(9):665–671. doi: 10.1096/fasebj.12.9.665. [DOI] [PubMed] [Google Scholar]
  47. Sumida C., Graber R., Nunez E. Role of fatty acids in signal transduction: modulators and messengers. Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):117–122. doi: 10.1016/0952-3278(93)90019-s. [DOI] [PubMed] [Google Scholar]
  48. Tabrizi S. J., Workman J., Hart P. E., Mangiarini L., Mahal A., Bates G., Cooper J. M., Schapira A. H. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol. 2000 Jan;47(1):80–86. doi: 10.1002/1531-8249(200001)47:1<80::aid-ana13>3.3.co;2-b. [DOI] [PubMed] [Google Scholar]
  49. Takeshita S., Inoue N., Ueyama T., Kawashima S., Yokoyama M. Shear stress enhances glutathione peroxidase expression in endothelial cells. Biochem Biophys Res Commun. 2000 Jun 24;273(1):66–71. doi: 10.1006/bbrc.2000.2898. [DOI] [PubMed] [Google Scholar]
  50. Taylor D. E., Ghio A. J., Piantadosi C. A. Reactive oxygen species produced by liver mitochondria of rats in sepsis. Arch Biochem Biophys. 1995 Jan 10;316(1):70–76. doi: 10.1006/abbi.1995.1011. [DOI] [PubMed] [Google Scholar]
  51. Thannickal V. J., Fanburg B. L. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1005–L1028. doi: 10.1152/ajplung.2000.279.6.L1005. [DOI] [PubMed] [Google Scholar]
  52. Turrens J. F. Superoxide production by the mitochondrial respiratory chain. Biosci Rep. 1997 Feb;17(1):3–8. doi: 10.1023/a:1027374931887. [DOI] [PubMed] [Google Scholar]
  53. Vacaresse N., Lajoie-Mazenc I., Augé N., Suc I., Frisach M. F., Salvayre R., Nègre-Salvayre A. Activation of epithelial growth factor receptor pathway by unsaturated fatty acids. Circ Res. 1999 Nov 12;85(10):892–899. doi: 10.1161/01.res.85.10.892. [DOI] [PubMed] [Google Scholar]
  54. Wallace D. C., Brown M. D., Melov S., Graham B., Lott M. Mitochondrial biology, degenerative diseases and aging. Biofactors. 1998;7(3):187–190. doi: 10.1002/biof.5520070303. [DOI] [PubMed] [Google Scholar]
  55. Wojtczak L., Schönfeld P. Effect of fatty acids on energy coupling processes in mitochondria. Biochim Biophys Acta. 1993 Nov 2;1183(1):41–57. doi: 10.1016/0005-2728(93)90004-y. [DOI] [PubMed] [Google Scholar]
  56. Zhou L. Z., Johnson A. P., Rando T. A. NF kappa B and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic Biol Med. 2001 Dec 1;31(11):1405–1416. doi: 10.1016/s0891-5849(01)00719-5. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES