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2024-05-20

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/219417

Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 

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https://doi.org/10.1093/brain/awae038

Resum

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.

Matèries

Malalties hereditàries, ADN mitocondrial, Axons

Matèries (anglès)

Genetic diseases, Mitochondrial DNA, Axons

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Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 . _Brain_. 2024. Vol. 147, núm. 6, pàgs. 2069-2084. [consulta: 22 de gener de 2026]. ISSN: 0006-8950. [Disponible a: https://hdl.handle.net/2445/219417]

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