title: Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency.
abstract: X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice.
authors.affiliation: Center for Brain Research, Medical University Vienna, Vienna, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Oezen
authors.forename: Walter
authors.initials: W
authors.lastname: Rossmanith
authors.forename: Sonja
authors.initials: S
authors.lastname: Forss-Petter
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.forename: Till
authors.initials: T
authors.lastname: Voigtländer
authors.forename: Karin
authors.initials: K
authors.lastname: Moser-Thier
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
authors.forename: Johannes
authors.initials: J
authors.lastname: Berger
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000032:analysis / Q000096:biosynthesis; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D002458:Cell Fractionation; D002478:Cells, Cultured; D003964:Diaphragm / Q000648:ultrastructure; D005230:Fatty Acids, Nonesterified / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000201:enzymology / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D019289:Pyruvic Acid / Q000378:metabolism; D012867:Skin / Q000166:cytology; D013347:Subcellular Fractions / Q000378:metabolism; D014960:X Chromosome
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005230:Fatty Acids, Nonesterified; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose