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

Maura Floreani, Eleonora Napoli, Andrea Martinuzzi, Giorgia Pantano, Valentina De Riva, Roberta Trevisan, Elena Bisetto, Lucia Valente, Valerio Carelli, Federica Dabbeni-Sala

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1124-1135
Number of pages12
JournalFEBS Journal
Volume272
Issue number5
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

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Leber's Hereditary Optic Atrophy
Mitochondrial DNA
Optics
Antioxidants
Glutathione Disulfide
Mutation
Oxidative stress
Glutathione Reductase
Galactose
Oxidative Stress
Glutathione Peroxidase
Superoxide Dismutase
Glucose
Detoxification
Mitochondria
Osteosarcoma
Point Mutation
Catalase
Free Radicals
Glutathione

Keywords

  • Antioxidant enzymes
  • Galactose medium
  • GSH and GSSG
  • Leber's hereditary optic neuropathy (LHON) cybrids
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry

Cite this

Floreani, M., Napoli, E., Martinuzzi, A., Pantano, G., De Riva, V., Trevisan, R., ... Dabbeni-Sala, F. (2005). Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy. FEBS Journal, 272(5), 1124-1135. https://doi.org/10.1111/j.1742-4658.2004.04542.x

Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy. / Floreani, Maura; Napoli, Eleonora; Martinuzzi, Andrea; Pantano, Giorgia; De Riva, Valentina; Trevisan, Roberta; Bisetto, Elena; Valente, Lucia; Carelli, Valerio; Dabbeni-Sala, Federica.

In: FEBS Journal, Vol. 272, No. 5, 01.03.2005, p. 1124-1135.

Research output: Contribution to journalArticle

Floreani, M, Napoli, E, Martinuzzi, A, Pantano, G, De Riva, V, Trevisan, R, Bisetto, E, Valente, L, Carelli, V & Dabbeni-Sala, F 2005, 'Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy', FEBS Journal, vol. 272, no. 5, pp. 1124-1135. https://doi.org/10.1111/j.1742-4658.2004.04542.x
Floreani, Maura ; Napoli, Eleonora ; Martinuzzi, Andrea ; Pantano, Giorgia ; De Riva, Valentina ; Trevisan, Roberta ; Bisetto, Elena ; Valente, Lucia ; Carelli, Valerio ; Dabbeni-Sala, Federica. / Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy. In: FEBS Journal. 2005 ; Vol. 272, No. 5. pp. 1124-1135.
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abstract = "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.",
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