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Lopez-Erauskin J.,Lhospitalet Of Llobregat | Lopez-Erauskin J.,University of Barcelona | Lopez-Erauskin J.,Center for Biomedical ResearchonRare Diseases | Galino J.,Lhospitalet Of Llobregat | And 26 more authors.
Human Molecular Genetics | Year: 2013

X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous systemcharacterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA. In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. We have formerly shown that an excess of the VLCFA C26:0 induces oxidative damage, which underlies the axonal degeneration exhibited by the Abcd1- mice. In the present study, we sought to investigate the noxious effects of C26:0 on mitochondria function. Ourdata indicate that in X-ALDpatients' fibroblasts,excessof C26:0 generatesmt DNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) triggering mitochondrialROSproduction from electron transport chain complexes. This correlates with impaired complex V phosphorylative activity, as visualized by high-resolution respirometry on spinal cord slices of Abcd1- mice. Further, we identified a marked oxidation of key OXPHOS system subunits in Abcd1- mouse spinal cords at presymptomatic stages. Altogether, our results illustratesomeof themechanistic intricacies bywhichthe excessof a fatty acid targeted to peroxisomesactivates a deleterious process of oxidative damage to mitochondria, leading to amultifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALD. © The Author 2013. Published by Oxford University Press. All rights reserved.

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