Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy
López Erauskin, Jone
Cuezva, J. M.
Cacabelos Barral, Daniel
Martínez, Juan José
MetadataShow full item record
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.
Is part ofHuman Molecular Genetics, 2013, vol. 22, núm. 16, p. 3296-3305
European research projects
Showing items related by title, author, creator and subject.
Morató, Laia; Ruiz, M.; Boada Pallàs, Jordi; Calingasan, Noel Ylagan; Galino, Jorge; Guilera, Cristina; Jové Font, Mariona; Naudí i Farré, Alba; Ferrer, Isidre; Pamplona Gras, Reinald; Serrano, M.; Portero Otín, Manuel; Beal, M. F.; Fourcade, Stéphane; Pujol, Aurora (Macmillan Publishers, 2015)Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the ...
Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS Cacabelos Barral, Daniel; Ramírez-Núñez, Omar; Granado-Serrano, Ana Belén; Torres Cabestany, Pascual; Ayala Jové, Ma. Victoria (Maria Victoria); Moiseeva, Victoria; Povedano, Mònica; Ferrer, Isidre; Pamplona Gras, Reinald; Portero Otín, Manuel; Boada Pallàs, Jordi (BioMed Central, 2016)Introduction: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a gender bias towards major prevalence in male individuals. Several data suggest the involvement of oxidative stress and mitochondrial dysfunction ...
Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance Fourcade, Stéphane; Morató, Laia; Parameswaran, Janani; Ruiz, Montserrat; Ruiz-Cortés, Tatiana; Jové Font, Mariona; Naudí i Farré, Alba; Martínez, Paloma; Dierssen, Mara; Ferrer, Isidre; Villarroya, Francesc; Pamplona Gras, Reinald; Vaquero, Alejandro; Portero Otín, Manuel; Pujol, Aurora (Wiley, 2017)Sirtuin 2 (SIRT2) is a member of a family of NAD+-dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and ...