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dc.contributor.authorLópez Erauskin, Jone
dc.contributor.authorGalino, Jorge
dc.contributor.authorRuiz, M.
dc.contributor.authorCuezva, J. M.
dc.contributor.authorFabregat, I.
dc.contributor.authorCacabelos Barral, Daniel
dc.contributor.authorBoada Pallàs, Jordi
dc.contributor.authorMartínez, Juan José
dc.contributor.authorFerrer, Isidre
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorVillarroya, Francesc
dc.contributor.authorPortero Otín, Manuel
dc.contributor.authorFourcade, Stéphane
dc.contributor.authorPujol, A.
dc.date.accessioned2016-11-15T08:28:45Z
dc.date.issued2013
dc.identifier.issn0964-6906
dc.identifier.urihttp://hdl.handle.net/10459.1/58502
dc.description.abstractX-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 (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. Our data indicate that in X-ALD patients' fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) 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.ca_ES
dc.description.sponsorshipThis study was supported by grants from the European Commission (FP7-241622), the European Leukodystrophy Association (ELA2009-036C5; ELA2008-040C4), the Spanish Institute for Health Carlos III (FIS PI080991 and FIS PI11/01043), the Autonomous Government of Catalonia (2009SGR85) to A.P. and the Spanish Institute for Health Carlos III (Miguel Servet program CP11/00080) to S.F. The CIBER on Rare Diseases (CIBERER) is an initiative of the ISCIII. The study was developed under the COST action BM0604 (to A.P.). J.L.-E. was a fellow of the Department of Education, Universities and Research of the Basque Country Government (BFI07.126). S.F. was a fellow of the European Leukodystrophy Association (ELA 2010-020F1). The studies conducted at the Department of Experimental Medicine were supported in part by R&D grants from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI), the Spanish Ministry of Health (PI11/ 1532), the Autonomous Government of Catalonia (2009SGR735), the ‘La Caixa’ Foundation and COST B35 Action of the European Union. D.C. is a fellow from the Spanish Ministry of Health (FI08-00707). The studies conducted at the Department of Biochemistry and Molecular Biology, University of Barcelona, were supported by grants SAF2008-01896 and SAF2011-23636 from the Spanish Ministry of Science and Innovation. The CIBER in Physiopathology of Obesity and Nutrition (CIBERobn) is an initiative of the ISCIII.ca_ES
dc.language.isoengca_ES
dc.publisherOxford Journalsca_ES
dc.relationMICINN/PN2008-2011/BFU2009-11879/BFI
dc.relationMICINN/PN2008-2011/SAF2008-01896
dc.relationMICINN/PN2008-2011/SAF2011-23636
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1093/hmg/ddt186ca_ES
dc.relation.ispartofHuman Molecular Genetics, 2013, vol. 22, núm. 16, p. 3296-3305ca_ES
dc.rights(c) Oxford Journals, 2013ca_ES
dc.titleImpaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophyca_ES
dc.typearticleca_ES
dc.identifier.idgrec020347
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_ES
dc.identifier.doihttps://doi.org/10.1093/hmg/ddt186
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/241622
dc.date.embargoEndDate2025-01-01


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