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Autor/a:
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López Erauskin, Jone; Galino, Jorge; Ruiz, M.; Cuezva, J. M.; Fabregat, I.; Cacabelos Barral, Daniel; Boada Pallàs, Jordi; Martínez, Juan José; Ferrer, Isidre; Pamplona Gras, Reinald; Villarroya, Francesc; Portero Otín, Manuel; Fourcade, Stéphane; Pujol, A.
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Notas:
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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 (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.
This 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. |
