title: 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.
abstract: 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.
authors.affiliation: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Straße 44, D-39120 Magdeburg, Germany.
authors.forename: Nicol
authors.initials: N
authors.lastname: Kruska
authors.affiliation: Institut für Biochemie und Zellbiologie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Straße 44, D-39120 Magdeburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schönfeld
authors.affiliation: Neurometabolic Diseases Laboratory, ICREA and Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Hospitalet de Llobregat 08908 Barcelona, Spain; Center for Biomedical Research in Rare Diseases (CIBERER), ISCIII Madrid, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Straße 44, D-39120 Magdeburg, Germany. Electronic address: georg.reiser@med.ovgu.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D009249:NADP; D002118:Calcium
keywords: Adrenoleukodystrophy (X-ALD); Astrocyte; Mitochondrion; Peroxisomal disorder; Reactive oxygen species; Very long chain fatty acids (VLCFA)