title: Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy.
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 (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.
authors.affiliation: Neurometabolic Diseases Laboratory, Institut d’Investigació Biomèdica de Bellvitge IDIBELL, L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: López-Erauskin
authors.forename: J
authors.initials: J
authors.lastname: Galino
authors.forename: M
authors.initials: M
authors.lastname: Ruiz
authors.forename: J M
authors.initials: JM
authors.lastname: Cuezva
authors.forename: I
authors.initials: I
authors.lastname: Fabregat
authors.forename: D
authors.initials: D
authors.lastname: Cacabelos
authors.forename: J
authors.initials: J
authors.lastname: Boada
authors.forename: J
authors.initials: J
authors.lastname: Martínez
authors.forename: I
authors.initials: I
authors.lastname: Ferrer
authors.forename: R
authors.initials: R
authors.lastname: Pamplona
authors.forename: F
authors.initials: F
authors.lastname: Villarroya
authors.forename: M
authors.initials: M
authors.lastname: Portero-Otín
authors.forename: S
authors.initials: S
authors.lastname: Fourcade
authors.forename: A
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004272:DNA, Mitochondrial; D005227:Fatty Acids / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D020675:Peroxisomes / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D004272:DNA, Mitochondrial; D005227:Fatty Acids; D005609:Free Radicals