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

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....

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Authors: 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, 1968-
Format: article
Status:Versión aceptada para publicación
Publication Date:2024
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/219417
Online Access:https://hdl.handle.net/2445/219417
Access Level:Open access
Keyword:Malalties hereditàries
ADN mitocondrial
Axons
Genetic diseases
Mitochondrial DNA
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spelling Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 Launay, NathalieLópez Erauskin, JoneBianchi, PatriziaGuha, SanjibParameswaran, JananiCoppa, AndreaTorreni, LorenzoSchlüter, AgathaFourcade, StéphaneParedes Fuentes, Abraham JoséArtuch, RafaelCasasnovas Pons, CarlosRuiz Sales, MontserratPujol, Aurora, 1968-Malalties hereditàriesADN mitocondrialAxonsGenetic diseasesMitochondrial DNAAxonsThe 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.Oxford University Press2025202520242025info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion48 p.application/pdfhttps://hdl.handle.net/2445/219417Articles publicats en revistes (Ciències Clíniques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1093/brain/awae038Brain, 2024, vol. 147, num.6, p. 2069-2084https://doi.org/10.1093/brain/awae038(c) Launay, N. et al., 2024info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2194172026-05-29T05:05:01Z
dc.title.none.fl_str_mv Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
title Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
spellingShingle Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
Launay, Nathalie
Malalties hereditàries
ADN mitocondrial
Axons
Genetic diseases
Mitochondrial DNA
Axons
title_short Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
title_full Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
title_fullStr Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
title_full_unstemmed Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
title_sort Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy                 
dc.creator.none.fl_str_mv 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, 1968-
author Launay, Nathalie
author_facet 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, 1968-
author_role author
author2 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, 1968-
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties hereditàries
ADN mitocondrial
Axons
Genetic diseases
Mitochondrial DNA
Axons
topic Malalties hereditàries
ADN mitocondrial
Axons
Genetic diseases
Mitochondrial DNA
Axons
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/219417
url https://hdl.handle.net/2445/219417
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1093/brain/awae038
Brain, 2024, vol. 147, num.6, p. 2069-2084
https://doi.org/10.1093/brain/awae038
dc.rights.none.fl_str_mv (c) Launay, N. et al., 2024
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Launay, N. et al., 2024
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 48 p.
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Clíniques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403237830885376
score 15,812429

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