Astrocytes and mitochondria from adrenoleukodystrophy protein (ABCD1)-deficient mice reveal that the adrenoleukodystrophy-associated very long-chain fatty acids target several cellular energy-dependent functions
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X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disorder resulting from defective ABCD1 transport protein. ABCD1 mediates peroxisomal uptake of free very-long-chain fatty acids (VLCFA) as well as their CoA-esters. Consequently, VLCFA accumulate in patients' plasma and tissues, which is considered as pathogenic X-ALD triggering factor. Clinical symptoms are mostly manifested in neural tissues and adrenal gland. Here, we investigate astrocytes from wild-type control and a genetic X-ALD mouse model (Abcd1-knockout), exposed to supraphysiological VLCFA (C22:0, C24:0 and C26:0) concentrations. They exhibit multiple impairments of energy metabolism. Furthermore, brain mitochondria from Abcd1(-/-) mice and wild-type control respond similarly to VLCFA with increased ROS generation, impaired oxidative ATP synthesis and diminished Ca(2+) uptake capacity, suggesting that a defective ABCD1 exerts no adaptive pressure on mitochondria. In contrast, astrocytes from Abcd1(-/-) mice respond more sensitively to VLCFA than wild-type control astrocytes. Moreover, long-term application of VLCFA induces high ROS generation, and strong in situ depolarization of mitochondria, and, in Abcd1(-/-) astrocytes, severely diminishes the capability to revert oxidized pyridine nucleotides to NAD(P)H. In addition, observed differences in responses of mitochondria and astrocytes to the hydrocarbon chain length of VLCFA suggest that detrimental VLCFA activities in astrocytes involve defective cellular functions other than mitochondria. In summary, we clearly demonstrate that VLCFA increase the vulnerability of Abcd1(-/-) astrocytes.
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Supraphysiological accumulation of C26:0 in astrocytes of ABCD1-deficient mice is followed by production of high reactive oxygen species.
“Similarly, supraphysiological accumulation of C26:0 in astrocytes of ABCD1-deficient mice is followed by production of high reactive oxygen species (15, 16).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [16]
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- Authors
- Kruska, N., Schönfeld, P., Pujol, A., & Reiser, G.
- Affiliations
- Otto-von-Guericke-Universität Magdeburg (DE)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Reiser, Georg
- ORCID
- Pujol, Aurora
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 1852
- Issue
- 5
- Pages
- 925-936
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2017092830
- Cited by
- 56
- References
- 16
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 2 · 2018: 3 · 2017: 9 · 2016: 5 · 2015: 6
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Instituto de Salud Carlos III
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- X-linked adrenoleukodystrophy, ABCD1, very long chain fatty acids, astrocytes, mitochondria, energy metabolism, reactive oxygen species, oxidative phosphorylation, calcium uptake, NAD(P)H regeneration, mitochondrial depolarization, fatty acid chain length
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Animals, Animals, Newborn, Astrocytes, Calcium, Cells, Cultured, Energy Metabolism, Fatty Acids, Mice, Inbred C57BL, Microscopy, Fluorescence, Mitochondria, NADP, Oxidative Phosphorylation, Spectrometry, Fluorescence, Ion Transport, Apoptosis, Reactive Oxygen Species, Thiobarbituric Acid Reactive Substances, Mice, Knockout, ATP-Binding Cassette Transporters, Membrane Potential, Mitochondrial
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