Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-Adrenoleukodystrophy

Thumbnail
View/Open
Issue date
2011
Author
Fourcade, Stéphane
Schlüter, Agatha
López Erauskin, Jone
Guilera, Cristina
Jové Font, Mariona
Naudí i Farré, Alba
García Arumí, Elena
Andreu, Antoni L.
Starkov, Anatoly A.
Pamplona Gras, Reinald
Ferrer, Isidre
Portero Otín, Manuel
Pujol, Aurora
Suggested citation
Fourcade, Stéphane; Schlüter, Agatha; López Erauskin, Jone; Guilera, Cristina; Jové Font, Mariona; Naudí i Farré, Alba; ... Pujol, Aurora. (2011) . Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-Adrenoleukodystrophy. Antioxidants and Redox Signaling, 2011, vol. 15, núm. 8, p. 2095-2108. https://doi.org/10.1089/ars.2010.3877.
Impact

Google Scholar logo  Google Scholar
Share
Export to Mendeley
Metadata
Show full item record
Abstract
Aims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits
axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1− mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1− mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107.
URI
http://hdl.handle.net/10459.1/58628
DOI
https://doi.org/10.1089/ars.2010.3877
Is part of
Antioxidants and Redox Signaling, 2011, vol. 15, núm. 8, p. 2095-2108
Collections