The role of mitochondrial glutathione in DNA base oxidation

Cecilia R Giulivi, Enrique Cadenas

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 purpose, 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 O2 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 mitochondria were similar. Succinate (in the absence or presence of antimycin A) enhanced the rate H2O2 production to a similar extent in both control and GSH-depleted mitochondria. These rates of H2O2 production accounted for 1.5-2.5% of the rate of O2 uptake. The levels of 8-HOdG in GSH-depleted mitochondria were 35-50% lower than those in control mitochondria, when measured at different H2O2 production rates. Conversely, in experiments carried out with calf thymus DNA with different Cu/Fe content, GSH increased 1.4-2.4-fold the accumulation of 8-HOdG. These values were further enhanced (44-50%) by superoxide dismutase and decreased by catalase. The lower levels of 8-HOdG in GSH-depleted mitochondria and the higher levels in GSH-supplemented calf thymus DNA suggest 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 O2, GSH, and metal catalysts bound to DNA. A mechanism is proposed by which GSH plays a critical role in the reduction of DNA-Cu complexes and decays by free radical pathways kinetically regulated by superoxide dismutase. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)265-274
Number of pages10
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1366
Issue number3
DOIs
StatePublished - Sep 7 1998
Externally publishedYes

Keywords

  • 8-Hydroxy-desoxyguanosine
  • Glutathione
  • Hydrogen peroxide
  • Mitochondria
  • Mitochondrial DNA
  • Oxidative stress

ASJC Scopus subject areas

  • Biophysics

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