![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
C Garcia-Ruiz, A Colell, A Morales, N Kaplowitz and JC Fernandez-Checa
Department of Medicine, Hospital Clinic i Provincial, Barcelona, Spain.
Mitochondria are an important source of reactive oxygen intermediates because they are the major consumers of molecular oxygen in cells. Respiration is associated with toxicity, which is related to the activation of oxygen to reactive intermediates. The purpose of the present study was to examine the role of reduced glutathione (GSH) in the maintenance of mitochondrial functions during oxidative stress induced through selective inhibition of the complex III segment of the electron transport chain. Hydrogen peroxide monitored by the fluorescence of dichlorofluorescein increased in a time- and dose- dependent manner on incubation of mitochondria with antimycin A (AA), an inhibitor of complex III. However, blockade of complex I or II with rotenone or thenoyltrifluoroacetone, respectively, did not result in accumulation of hydrogen peroxide. Depletion of mitochondrial GSH to 10- 20% of control by preincubation with diethylmaleate (0.8 mM) or ethacrynic acid (250 microM) also increased dichlorofluorescein and malondialdehyde levels and resulted in an additional (2-3-fold) increase after AA. Similar results were obtained when mitochondrial GSH depletion was produced by treatment with buthionine L-sulfoximine before mirochondria isolation. The endogenous oxidative stress induced by AA was accompanied by a moderate loss of activity of ATPase complex (77% of control) and complex IV of respiration (75% of control), which was accentuated after depletion of mitochondrial GSH (51% and 45% of control, respectively). Similar results were observed in isolated hepatocytes in which depletion of mitochondrial GSH and AA led to peroxidation and mitochondrial dysfunction. In addition, with electrophoretic mobility shift assay of the transcription factor nuclear factor-kappa B (NF-kappa B), we detected its activation in response to AA (2-3-fold). Depletion of mitochondrial GSH in hepatocytes (20% of control) led to further enhancement of NF-kappa B activation (2-4-fold), which correlated with generation of hydrogen peroxide. Thus, our results suggest that GSH protects mitochondria against the endogenous oxidative stress produced at the ubiquinone site of the electron transport chain. Mitochondrial GSH depletion potentiates oxidant-induced loss of mitochondrial functions. Oxidant stress in mitochondria can promote extramitochondrial activation of NF- kappa B and therefore may affect nuclear gene expression.
This article has been cited by other articles:
|
|
 |
|
  H. Lou and N. Kaplowitz Glutathione Depletion Down-regulates Tumor Necrosis Factor {alpha}-induced NF-{kappa}B Activity via I{kappa}B Kinase-dependent and -independent Mechanisms J. Biol. Chem., October 5, 2007; 282(40): 29470 - 29481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kohli, X. Pan, P. Malladi, M. S. Wainwright, and P. F. Whitington Mitochondrial Reactive Oxygen Species Signal Hepatocyte Steatosis by Regulating the Phosphatidylinositol 3-Kinase Cell Survival Pathway J. Biol. Chem., July 20, 2007; 282(29): 21327 - 21336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-C. Lee and Y.-H. Wei Oxidative Stress, Mitochondrial DNA Mutation, and Apoptosis in Aging Experimental Biology and Medicine, May 1, 2007; 232(5): 592 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.M. Payne, C. Weber, C. Crowley-Skillicorn, K. Dvorak, H. Bernstein, C. Bernstein, H. Holubec, B. Dvorakova, and H. Garewal Deoxycholate induces mitochondrial oxidative stress and activates NF-{kappa}B through multiple mechanisms in HCT-116 colon epithelial cells Carcinogenesis, January 1, 2007; 28(1): 215 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang, L. M. Schumaker, M. J. Egorin, E. G. Zuhowski, Z. Guo, and K. J. Cullen Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clin. Cancer Res., October 1, 2006; 12(19): 5817 - 5825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Hansen, H. Zhang, and D. P. Jones Mitochondrial Thioredoxin-2 Has a Key Role in Determining Tumor Necrosis Factor-{alpha}-Induced Reactive Oxygen Species Generation, NF-{kappa}B Activation, and Apoptosis Toxicol. Sci., June 1, 2006; 91(2): 643 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Esposito, J. Raber, L. Kekonius, F. Yan, G.-Q. Yu, N. Bien-Ly, J. Puolivali, K. Scearce-Levie, E. Masliah, and L. Mucke Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J. Neurosci., May 10, 2006; 26(19): 5167 - 5179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Griguer, C. R. Oliva, E. E. Kelley, G. I. Giles, J. R. Lancaster Jr., and G. Y. Gillespie Xanthine Oxidase-Dependent Regulation of Hypoxia-Inducible Factor in Cancer Cells Cancer Res., February 15, 2006; 66(4): 2257 - 2263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Couillard and C. Prefaut From muscle disuse to myopathy in COPD: potential contribution of oxidative stress Eur. Respir. J., October 1, 2005; 26(4): 703 - 719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ghosh, T. Pulinilkunnil, G. Yuen, G. Kewalramani, D. An, D. Qi, A. Abrahani, and B. Rodrigues Cardiomyocyte apoptosis induced by short-term diabetes requires mitochondrial GSH depletion Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H768 - H776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Basta, G. Lazzerini, S. Del Turco, G. M. Ratto, A. M. Schmidt, and R. De Caterina At Least 2 Distinct Pathways Generating Reactive Oxygen Species Mediate Vascular Cell Adhesion Molecule-1 Induction by Advanced Glycation End Products Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1401 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Lluis, A. Morales, C. Blasco, A. Colell, M. Mari, C. Garcia-Ruiz, and J. C. Fernandez-Checa Critical Role of Mitochondrial Glutathione in the Survival of Hepatocytes during Hypoxia J. Biol. Chem., February 4, 2005; 280(5): 3224 - 3232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Singh, A. Herman-Antosiewicz, A. V. Singh, K. L. Lew, S. K. Srivastava, R. Kamath, K. D. Brown, L. Zhang, and R. Baskaran Sulforaphane-induced G2/M Phase Cell Cycle Arrest Involves Checkpoint Kinase 2-mediated Phosphorylation of Cell Division Cycle 25C J. Biol. Chem., June 11, 2004; 279(24): 25813 - 25822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Raza, S. K. Prabu, M.-A. Robin, and N. G. Avadhani Elevated Mitochondrial Cytochrome P450 2E1 and Glutathione S-Transferase A4-4 in Streptozotocin-Induced Diabetic Rats: Tissue-Specific Variations and Roles in Oxidative Stress Diabetes, January 1, 2004; 53(1): 185 - 194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Delsite, L. J. Rasmussen, A. K. Rasmussen, A. Kalen, P. C. Goswami, and K. K. Singh Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus Mutagenesis, November 1, 2003; 18(6): 497 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Han, R. Canali, D. Rettori, and N. Kaplowitz Effect of Glutathione Depletion on Sites and Topology of Superoxide and Hydrogen Peroxide Production in Mitochondria Mol. Pharmacol., November 1, 2003; 64(5): 1136 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Vergauwen, F. Pauwels, and J. J. Van Beeumen Glutathione and Catalase Provide Overlapping Defenses for Protection against Respiration-Generated Hydrogen Peroxide in Haemophilus influenzae J. Bacteriol., September 15, 2003; 185(18): 5555 - 5562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Rudin, Z. Yang, L. M. Schumaker, D. J. VanderWeele, K. Newkirk, M. J. Egorin, E. G. Zuhowski, and K. J. Cullen Inhibition of Glutathione Synthesis Reverses Bcl-2-mediated Cisplatin Resistance Cancer Res., January 15, 2003; 63(2): 312 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Wei and H.-C. Lee Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging Experimental Biology and Medicine, October 1, 2002; 227(9): 671 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-E. HARPER, A. ANTONIOU, E. VILLALOBOS-MENUEY, A. RUSSO, R. TRAUGER, M. VENDEMELIO, A. GEORGE, R. BARTHOLOMEW, D. CARLO, A. SHAIKH, et al. Characterization of a novel metabolic strategy used by drug-resistant tumor cells FASEB J, October 1, 2002; 16(12): 1550 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Seme, P. Summerfelt, J. Neitz, J. T. Eells, and M. M. Henry Differential Recovery of Retinal Function after Mitochondrial Inhibition by Methanol Intoxication Invest. Ophthalmol. Vis. Sci., March 1, 2001; 42(3): 834 - 841. [Abstract] [Full Text]
|
|
|
|
|
|
J. P. Kehrer and S. S. Biswal The Molecular Effects of Acrolein Toxicol. Sci., September 1, 2000; 57(1): 6 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Phillips, A. J. Williams, J. Adams, P. J. Elliott, F. C. Tortella, and J. A. Clemens Proteasome Inhibitor PS519 Reduces Infarction and Attenuates Leukocyte Infiltration in a Rat Model of Focal Cerebral Ischemia Editorial Comment Stroke, July 1, 2000; 31(7): 1686 - 1693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Roman, A. Gimenez, J. M. Lluis, M. Gasso, M. Rubio, J. Caballeria, A. Pares, J. Rodes, and J. C. Fernandez-Checa Enhanced DNA Binding and Activation of Transcription Factors NF-kappa B and AP-1 by Acetaldehyde in HEPG2 Cells J. Biol. Chem., May 5, 2000; 275(19): 14684 - 14690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. GARCÍA-RUIZ, A. COLELL, R. PARÍS, and J. C. FERNÁNDEZ-CHECA Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation FASEB J, May 1, 2000; 14(7): 847 - 858. [Abstract] [Full Text]
|
|
|
|
|
|
P. Poli, A. Buschini, A. Candi, and C. Rossi Bleomycin genotoxicity alteration by glutathione and cytochrome P-450 cellular content in respiratory proficient and deficient strains of Saccharomyces cerevisiae Mutagenesis, March 1, 1999; 14(2): 233 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Arai, H. Imai, T. Koumura, M. Yoshida, K. Emoto, M. Umeda, N. Chiba, and Y. Nakagawa Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase Plays a Major Role in Preventing Oxidative Injury to Cells J. Biol. Chem., February 19, 1999; 274(8): 4924 - 4933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. O'Donovan, J. P. Katkin, T. Tamura, R. Husser, X. Xu, C. V. Smith, and S. E. Welty Gene Transfer of Mitochondrially Targeted Glutathione Reductase Protects H441 Cells from t-Butyl Hydroperoxide-Induced Oxidant Stresses Am. J. Respir. Cell Mol. Biol., February 1, 1999; 20(2): 256 - 263. [Abstract] [Full Text]
|
|
|
|
|
|
M. Carballo, G. Marquez, M. Conde, J. Martin-Nieto, J. Monteseirin, J. Conde, E. Pintado, and F. Sobrino Characterization of Calcineurin in Human Neutrophils. INHIBITORY EFFECT OF HYDROGEN PEROXIDE ON ITS ENZYME ACTIVITY AND ON NF-kappa B DNA BINDING J. Biol. Chem., January 1, 1999; 274(1): 93 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Williams, H. Van Remmen, C. C. Conrad, T. T. Huang, C. J. Epstein, and A. Richardson Increased Oxidative Damage Is Correlated to Altered Mitochondrial Function in Heterozygous Manganese Superoxide Dismutase Knockout Mice J. Biol. Chem., October 23, 1998; 273(43): 28510 - 28515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S. Chandel, E. Maltepe, E. Goldwasser, C. E. Mathieu, M. C. Simon, and P. T. Schumacker Mitochondrial reactive oxygen species trigger hypoxia-induced transcription PNAS, September 29, 1998; 95(20): 11715 - 11720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Spolarics and J.-X. Wu Role of glutathione and catalase in H2O2 detoxification in LPS-activated hepatic endothelial and Kupffer cells Am J Physiol Gastrointest Liver Physiol, December 1, 1997; 273(6): G1304 - G1311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Morales, C. Garcia-Ruiz, M. Miranda, M. Mari, A. Colell, E. Ardite, and J. C. Fernandez-Checa Tumor Necrosis Factor Increases Hepatocellular Glutathione by Transcriptional Regulation of the Heavy Subunit Chain of gamma -Glutamylcysteine Synthetase J. Biol. Chem., November 28, 1997; 272(48): 30371 - 30379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Quillet-Mary, J.-P. Jaffrezou, V. Mansat, C. Bordier, J. Naval, and G. Laurent Implication of Mitochondrial Hydrogen Peroxide Generation in Ceramide-induced Apoptosis J. Biol. Chem., August 22, 1997; 272(34): 21388 - 21395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Garcia-Ruiz, A. Colell, M. Mari, A. Morales, and J. C. Fernandez-Checa Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species. ROLE OF MITOCHONDRIAL GLUTATHIONE J. Biol. Chem., April 25, 1997; 272(17): 11369 - 11377. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
