title: Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy.
abstract: Peroxisomal disorders have been associated with malfunction of peroxisomal metabolic pathways, but the pathogenesis of these disorders is largely unknown. X-linked adrenoleukodystrophy (X-ALD) is associated with elevated levels of very-long-chain fatty acids (VLCFA; C(>22:0)) that have been attributed to reduced peroxisomal VLCFA beta-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA beta-oxidation in human and mouse X-ALD fibroblasts. In this study, we found normal levels of peroxisomal VLCFA beta-oxidation in tissues from ALD mice with elevated VLCFA levels. Treatment of ALD mice with pharmacological agents resulted in decreased VLCFA levels without a change in VLCFA beta-oxidation activity. These data indicate that ALDP does not determine the rate of VLCFA beta-oxidation and that VLCFA levels are not determined by the rate of VLCFA beta-oxidation. The rate of peroxisomal VLCFA beta-oxidation in human and mouse fibroblasts in vitro is affected by the rate of mitochondrial long-chain fatty acid beta-oxidation. We hypothesize that ALDP facilitates the interaction between peroxisomes and mitochondria, resulting, when ALDP is deficient in X-ALD, in increased VLCFA accumulation despite normal peroxisomal VLCFA beta-oxidation in ALD mouse tissues. In support of this hypothesis, mitochondrial structural abnormalities were observed in adrenal cortical cells of ALD mice.
authors.affiliation: Kennedy Krieger Institute and Departments of Neurology, Baltimore, Maryland 21205, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: McGuinness
authors.forename: J-F
authors.initials: JF
authors.lastname: Lu
authors.forename: H-P
authors.initials: HP
authors.lastname: Zhang
authors.forename: G-X
authors.initials: GX
authors.lastname: Dong
authors.forename: A K
authors.initials: AK
authors.lastname: Heinzer
authors.forename: P A
authors.initials: PA
authors.lastname: Watkins
authors.forename: J
authors.initials: J
authors.lastname: Powers
authors.forename: K D
authors.initials: KD
authors.lastname: Smith
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000311:Adrenal Glands / Q000648:ultrastructure; D000326:Adrenoleukodystrophy / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D010100:Oxygen