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Molecular and Cellular Biology, January 2003, p. 744-753, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.744-753.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy

M. C. McGuinness,1 J.-F. Lu,2 H.-P. Zhang,3 G.-X. Dong,3 A. K. Heinzer,2 P. A. Watkins,1 J. Powers,4 and K. D. Smith2,3*

Kennedy Krieger Institute and Departments of Neurology,1 Pediatrics,3 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,2 Department of Pathology, University of Rochester, Rochester, New York4

Received 23 May 2002/ Returned for modification 7 October 2002/ Accepted 23 October 2002

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 ß-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA ß-oxidation in human and mouse X-ALD fibroblasts. In this study, we found normal levels of peroxisomal VLCFA ß-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 ß-oxidation activity. These data indicate that ALDP does not determine the rate of VLCFA ß-oxidation and that VLCFA levels are not determined by the rate of VLCFA ß-oxidation. The rate of peroxisomal VLCFA ß-oxidation in human and mouse fibroblasts in vitro is affected by the rate of mitochondrial long-chain fatty acid ß-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 ß-oxidation in ALD mouse tissues. In support of this hypothesis, mitochondrial structural abnormalities were observed in adrenal cortical cells of ALD mice.

* Corresponding author. Mailing address: Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205. Phone: (443) 923-2751. Fax: (443) 923-2752. E-mail: smithk{at}jhmi.edu.

Molecular and Cellular Biology, January 2003, p. 744-753, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.744-753.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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