Kruska 2015 Biochim Biophys Acta

Kruska N, Schönfeld P, Pujol A, Reiser G (2015) 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. Biochim Biophys Acta 1852:925-36.

» PMID:25583114

Kruska N, Schoenfeld P, Pujol A, Reiser G (2015) Biochim Biophys Acta

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 energymetabolism. Furthermore, brain mitochondria from Abcd1−/−mice and wild-type control respond similarly to VLCFAwith increased ROS generation, impaired oxidative ATP synthesis and diminished Ca²⁺ 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, longterm 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. • Keywords: Adrenoleukodystrophy (X-ALD), Astrocyte, Mitochondrion, Peroxisomal disorder, Reactive oxygen species, Very long chain fatty acids (VLCFA), Amplex Red

• O2k-Network Lab: DE Magdeburg Schoenfeld P

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Other  Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 

Regulation: Calcium  Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k