Lopez-Erauskin 2013 Hum Mol Genet

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López-Erauskin J, Galino J, Ruiz M, Cuezva JM, Fabregat I, Cacabelos D, Boada J, Martínez J, Ferrer I, Pamplona R, Villarroya F, Portero-Otín M, Fourcade S, Pujol A (2013) Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum Mol Genet 22:3296-305.

» PMID: 23604518 Open Access

Lopez-Erauskin J, Galino J, Ruiz M, Cuezva JM, Fabregat I, Cacabelos D, Boada J, Martinez J, Ferrer I, Pamplona R, Villarroya F, Portero-Otin M, Fourcade S, Pujol A (2013) Hum Mol Genet

Abstract: X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous system characterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFA 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. Our data indicate that in X-ALD patients' fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation triggering mitochondrial ROS production 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 illustrate some of the mechanistic intricacies by which the excess of a fatty acid targeted to peroxisomes, activates a deleterious process of oxidative damage to mitochondria, leading to a multifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALD.

Keywords: X-linked adrenoleukodystrophy, Mitochondrial respiration, Axonal degeneration, Oxidative stress, Very long-chain fatty acids

O2k-Network Lab: ES Lleida Boada J


Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS, Mitochondrial disease  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Permeabilized tissue 

Regulation: Fatty acid 


HRR: Oxygraph-2k