Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy
Open accessAbstract
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.
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Experimental results from A. Pujol's laboratory demonstrated overproduction of redox free radicals altering mitochondrial functions in brain white matter or cultured cells.
“Experimental results from A. Pujol’s laboratory demonstrated overproduction of redox free radicals altering mitochondrial functions in brain white matter or cultured cells [80,136,179,180,181,182,183,184,185,186,187,188,189].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [179]
This adaptive metabolic homeostasis renders unlikely the hypothesis of mitochondrial energy deficiency as a primary mechanism of axonal degeneration in cALD or AMN.
“This adaptive metabolic homeostasis renders unlikely the hypothesis of mitochondrial energy deficiency as a primary mechanism of axonal degeneration in cALD or AMN [179,181,182,288].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [179]
Cites
Mitochondrial dysfunction in cell senescence and aging
Miwa, S., Kashyap, S., Chini, E., & von Zglinicki, T. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158447 · Cited by 1,061 · see citing works
Mitochondrial fusion and fission: The fine‐tune balance for cellular homeostasis
Adebayo, M., Singh, S., Singh, A. P., & Dasgupta, S. (2021) · The FASEB Journal · doi:10.1096/fj.202100067r · Cited by 733 · see citing works
The Peroxisome-Mitochondria Connection: How and Why?
Fransen, M., Lismont, C., & Walton, P. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061126 · Cited by 351 · see citing works
A mouse model for X-linked adrenoleukodystrophy
Lu, J.-F., Lawler, A. M., Watkins, P. A., Powers, J. M., Moser, A. B., Moser, H. W., & Smith, K. D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.17.9366 · Cited by 293 · see citing works
Adrenoleukodystrophy—Neuroendocrine pathogenesis and redefinition of natural history
Kemp, S., Huffnagel, I. C., Linthorst, G. E., Wanders, R. J., & Engelen, M. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.90 · Cited by 275 · see citing works
Computational classification of mitochondrial shapes reflects stress and redox state
Ahmad, T., Aggarwal, K., Pattnaik, B., Mukherjee, S., Sethi, T., Tiwari, B. K., Kumar, M., Micheal, A., Mabalirajan, U., Ghosh, B., et al. (2013) · Cell Death & Disease · doi:10.1038/cddis.2012.213 · Cited by 233 · see citing works
Pujol, A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.499 · Cited by 214 · see citing works
Self-citationPujol, A., Ferrer, I., Camps, C., Metzger, E., Hindelang, C., Callizot, N., Ruiz, M., Pàmpols, T., Giròs, M., & Mandel, J. L. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh323 · Cited by 201 · see citing works
Self-citationX-Linked Adrenoleukodystrophy: Pathogenesis and Treatment
Engelen, M., Kemp, S., & Poll-The, B.-T. (2014) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-014-0486-0 · Cited by 187 · see citing works
Koch, J., Feichtinger, R. G., Freisinger, P., Pies, M., Schrödl, F., Iuso, A., Sperl, W., Mayr, J. A., Prokisch, H., & Haack, T. B. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2015-103500 · Cited by 127 · see citing works
Ferrer, I., Kapfhammer, J. P., Hindelang, C., Kemp, S., Troffer-Charlier, N., Broccoli, V., Callyzot, N., Mooyer, P., Selhorst, J., Vreken, P., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi384 · Cited by 106 · see citing works
Self-citationFourcade, S., López-Erauskin, J., Ruiz, M., Ferrer, I., & Pujol, A. (2014) · Biochimie · doi:10.1016/j.biochi.2013.09.012 · Cited by 55 · see citing works
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Launay, N., Lopez-Erauskin, J., Bianchi, P., Guha, S., Parameswaran, J., Coppa, A., Torreni, L., Schlüter, A., Fourcade, S., Paredes-Fuentes, A. J., Artuch, R., Casasnovas, C., Ruiz, M., & Pujol, A.
- Affiliations
- Instituto de Salud Carlos III (ES)
- Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL , 08908 L’Hospitalet de Llobregat, Barcelona , Spain
- Universitat Autònoma de Barcelona (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Emory University (US)
- Hospital Clínic de Barcelona (ES)
- Hospital Sant Joan de Déu Barcelona (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Pujol, Aurora
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2024-05-20
- Volume
- 147
- Issue
- 6
- Pages
- 2069-2084
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W4397293932
- Cited by
- 14
- References
- 12
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- Centro de Investigación biomedica en Red- Enfermedades Rares
- Instituto de Salud Carlos III
- European Regional Development Fund
- Generalitat de Catalunya
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- X-linked adrenoleukodystrophy, mitochondrial dynamics, mitochondrial fragmentation, Drp1, very long chain fatty acids, ABCD1, peroxisomal dysfunction, corticospinal axons, axonal integrity, cerebrospinal fluid, therapeutic target, Caenorhabditis elegans model
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Animals, Axons, Disease Models, Animal, DNA, Mitochondrial, Fibroblasts, Humans, Male, Mitochondria, Peptide Fragments, Pyramidal Tracts, Caenorhabditis elegans, GTP Phosphohydrolases, Dynamins, Mice, Mitochondrial Dynamics
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