THE ROLE OF MITOCHONDRIAL GLUTATHIONE IN DNA-BASE OXIDATION

Citation
C. Giulivi et E. Cadenas, THE ROLE OF MITOCHONDRIAL GLUTATHIONE IN DNA-BASE OXIDATION, Biochimica et biophysica acta. Bioenergetics, 1366(3), 1998, pp. 265-274
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biology,Biophysics
ISSN journal
0005-2728
Volume
1366
Issue
3
Year of publication
1998
Pages
265 - 274
Database
ISI
SICI code
0005-2728(1998)1366:3<265:TROMGI>2.0.ZU;2-4
Abstract
The objective of this study was to elucidate the role of mitochondrial GSH in the reactions leading to mitochondrial DNA oxidative damage in terms of 8-hydroxy-desoxyguanosine (8-HOdG) accumulation. With this p urpose, tightly coupled mitochondria depleted of matrix GSH were used and the effects of H2O2 (generated during the oxidation of substrates) on 8-HOdG levels were investigated. Mitochondrial integrity, assessed by Oz uptake, respiratory control and P/O ratios, was conserved upon depletion of GSH up to 95%. The rates of H2O2 production linked to the oxidation of endogenous substrates by control and GSH-depleted mitoch ondria were similar. Succinate (in the absence or presence of antimyci n A) enhanced the rate H2O2 production to a similar extent in both con trol and GSH-depleted mitochondria. These rates of H2O2 production acc ounted for 1.5-2.5% of the rate of O-2 uptake. The levels of 8-HOdG in GSH-depleted mitochondria were 35-50% lower than those in control mit ochondria, when measured at different H2O2 production rates. Conversel y, in experiments carried out with calf thymus DNA with different Cu/F e content, GSH increased 1.4-2.4-fold the accumulation of 8-HOdG. Thes e values were further enhanced (44-50%) by superoxide dismutase and de creased by catalase. The lower levels of s-HOdG in GSH-depleted mitoch ondria and the higher levels in GSH-supplemented calf thymus DNA sugge st a role for the non-protein thiol in the reactions leading to mtDNA oxidative damage. These findings are interpreted in terms of the redox transitions involving O-2, GSH, and metal catalysts bound to DNA. A m echanism is proposed by which GSH plays a critical role in the reducti on of DNA-Cu complexes and decays by free radical pathways kinetically regulated by superoxide dismutase. (C) 1998 Elsevier Science B.V. All rights reserved.