Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy

FEBS J. 2005 Mar;272(5):1124-35. doi: 10.1111/j.1742-4658.2004.04542.x.


Oxidative stress and imbalance between free radical generation and detoxification may play a pivotal role in the pathogenesis of Leber's hereditary optic neuropathy (LHON). Mitochondria, carrying the homoplasmic 11778/ND4, 3460/ND1 and 14484/ND6 mtDNA point mutations associated with LHON, were used to generate osteosarcoma-derived cybrids. Enhanced mitochondrial production of reactive oxygen species has recently been demonstrated in these cybrids [Beretta S, Mattavelli L, Sala G, Tremolizzo L, Schapira AHV, Martinuzzi A, Carelli V & Ferrarese C (2004) Brain 127, 2183-2192]. The aim of this study was to characterize the antioxidant defences of these LHON-affected cells. The activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutases (SOD) and catalase, and the amounts of glutathione (GSH) and oxidized glutathione (GSSG) were measured in cybrids cultured both in glucose-rich medium and galactose-rich medium. The latter is known to cause oxidative stress and to trigger apoptotic death in these cells. In spite of reduced SOD activities in all LHON cybrids, and of low GPx and GR activities in cells with the most severe 3460/ND1 and 11778/ND4 mutations, GSH and GSSG content were not significantly modified in LHON cybrids cultured in glucose medium. In contrast, in galactose, GSSG concentrations increased significantly in all cells, indicating severe oxidative stress, whereas GR and MnSOD activities further decreased in all LHON cybrids. These data suggest that, in cells carrying LHON mutations, there is a decrease in antioxidant defences, which is especially evident in cells with mutations associated with the most severe clinical phenotype. This is magnified by stressful conditions such as exposure to galactose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism*
  • Case-Control Studies
  • Catalase / metabolism
  • Cells, Cultured
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics*
  • Fibroblasts / metabolism
  • Galactose / metabolism
  • Glucose / metabolism
  • Glutathione / metabolism
  • Glutathione Peroxidase / metabolism
  • Glutathione Reductase / metabolism
  • Humans
  • Hybrid Cells / metabolism*
  • Hybrid Cells / pathology
  • Mitochondria / metabolism
  • Mutation / genetics*
  • Optic Atrophy, Hereditary, Leber / genetics*
  • Oxygen / metabolism*
  • Skin / metabolism
  • Superoxide Dismutase / metabolism


  • Antioxidants
  • DNA, Mitochondrial
  • Catalase
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Glutathione Reductase
  • Glutathione
  • Glucose
  • Oxygen
  • Galactose