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: Nicol Kruska, Peter Schönfeld, Aurora Pujol, Georg Reiser
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1852 Issue 5 Pg. 925-36 (May 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25583114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters
• Abcd1 protein, mouse
• Fatty Acids
• Reactive Oxygen Species
• Thiobarbituric Acid Reactive Substances
• NADP
• Calcium

Topics

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters (deficiency, genetics)
• Adrenoleukodystrophy (genetics, metabolism)
• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Astrocytes (drug effects, metabolism)
• Calcium (metabolism, pharmacokinetics)
• Cells, Cultured
• Energy Metabolism (drug effects)
• Fatty Acids (chemistry, pharmacology)
• Ion Transport (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Fluorescence
• Mitochondria (drug effects, metabolism)
• NADP (metabolism)
• Oxidative Phosphorylation (drug effects)
• Reactive Oxygen Species (metabolism)
• Spectrometry, Fluorescence
• Thiobarbituric Acid Reactive Substances (metabolism)