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Kruska N.,Otto Von Guericke University of Magdeburg | Schonfeld P.,Otto Von Guericke University of Magdeburg | Pujol A.,Catalan Institution for Research and Advanced Studies | Pujol A.,Center for Biomedical Research in Rare Diseases | Reiser G.,Otto Von Guericke University of Magdeburg
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2015

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 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, 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. © 2015 Elsevier B.V. Source


Ormazabal A.,Center for Biomedical Research in Rare Diseases | Casado M.,Center for Biomedical Research in Rare Diseases | Molero-Luis M.,Center for Biomedical Research in Rare Diseases | Molero-Luis M.,CIBER ISCIII | And 12 more authors.
Drug Discovery Today | Year: 2015

Cellular folate metabolism is highly compartmentalized, with mitochondria folate transport and metabolism being distinct from the well-known cytosolic folate metabolism. There is evidence supporting the association between low folate status and mitochondrial DNA (mtDNA) instability, and cerebral folate deficiency is relatively frequent in mitochondrial disorders. Furthermore, folinic acid supplementation has been reported to be beneficial not only in some patients with mitochondrial disease, but also in patients with relatively common diseases where folate deficiency might be an important pathophysiological factor. In this review, we focus on the evidence that supports the potential involvement of impaired folate metabolism in the pathophysiology of mitochondrial disorders. ©2015 Elsevier Ltd. All rights reserved. Source

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