Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/219417
Title: Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
Author: Launay, Nathalie
López Erauskin, Jone
Bianchi, Patrizia
Guha, Sanjib
Parameswaran, Janani
Coppa, Andrea
Torreni, Lorenzo
Schlüter, Agatha
Fourcade, Stéphane
Paredes Fuentes, Abraham José
Artuch, Rafael
Casasnovas Pons, Carlos
Ruiz Sales, Montserrat
Pujol, Aurora
Keywords: Malalties hereditàries
ADN mitocondrial
Axons
Genetic diseases
Mitochondrial DNA
Axons
Issue Date: 20-May-2024
Publisher: Oxford University Press
Abstract: The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
Note: Versió postprint del document publicat a: https://doi.org/10.1093/brain/awae038
It is part of: Brain, 2024, vol. 147, num.6, p. 2069-2084
URI: https://hdl.handle.net/2445/219417
Related resource: https://doi.org/10.1093/brain/awae038
ISSN: 0006-8950
Appears in Collections:Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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