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

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.

• Authors: Jorge Galino, Montserrat Ruiz, Stéphane Fourcade, Agatha Schlüter, Jone López-Erauskin, Cristina Guilera, Mariona Jove, Alba Naudi, Elena García-Arumí, Antoni L Andreu, Anatoly A Starkov, Reinald Pamplona, Isidre Ferrer, Manuel Portero-Otin, Aurora Pujol
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 15 Issue 8 Pg. 2095-107 (Oct 15 2011) ISSN: 1557-7716 [Electronic] United States
• PMID: 21453200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters
• Abcd1 protein, mouse
• NAD
• Adenosine Triphosphate
• Pyruvate Kinase
• Glutathione

Topics

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Adenosine Triphosphate (metabolism)
• Adrenoleukodystrophy (genetics, metabolism)
• Animals
• Blotting, Western
• Cells, Cultured
• Disease Models, Animal
• Electrophoresis, Gel, Two-Dimensional
• Energy Metabolism (genetics, physiology)
• Glutathione (metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• NAD (metabolism)
• Oxidative Stress (genetics, physiology)
• Proteomics
• Pyruvate Kinase (genetics, metabolism)