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

McGuinness, Mark; Lu, Jyh-Feng; Zhang, H.-P.; Dong, Gao-xiang; Heinzer, Ann K.; Watkins, Paul A.; Powers, James M.; Smith, Kirby D.

doi:10.1128/mcb.23.2.744-753.2003

Cited by 129 publications

(88 citation statements)

References 42 publications

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“…8 Recent studies of the abcd1 KO mouse in our laboratory have revealed some interesting and surprising findings. 13,14 (1) While elevated levels of VLCFA remain the biochemical signature of ALD/AMN, it is clear that this is not due to a deficiency in peroxisomal VLCFA degradation, as was previously believed. (2) The rate of peroxisomal b-oxidation of VLCFA in cultured fibroblasts is directly related to the rate of mitochondrial long-chain fatty acid b-oxidation.…”

mentioning

confidence: 82%

“…Conversely, the accelerated course of ceroid deposition when abcd2 is absent appears to be slowed somewhat by 4-PBA treatment, which previously was shown to augment mitochondrial activity in the abcd1 KO. 13,14 Thus, it is reasonable to conclude that damaged mitochondria are a major contributor to these ceroids. The abcd2 KO fibroblast cultures also support this conclusion (see Figure 6b).…”

Section: Discussionmentioning

confidence: 99%

“…4-PBA has been shown to improve the saturated fatty acid defect in ALD and abcd1 KO fibroblasts. 13,14 Two ceroid-positive 21-month-old male abcd2 KO mice were stained with the Bodian silver protargol method and immunostained for synaptophysin (a medullary cell marker; rabbit monoclonal, 1:600; Neomarkers, Fremont, CA, USA), F4/80 (a mouse macrophage marker; rat monoclonal, 1:50 with heat retrieval; Caltag, Burlingame, CA), activated caspase-3, (polyclonal, 1:1000; R & D Systems, Minneapolis, MN, USA), heme oxygenase-1 (HO-1; polyclonal, 1:2000 with heat retrieval; Stressgen, Victoria, BC, Canada), HNE (polyclonal, 1:2750 with heat retrieval; Calbiochem, LaJolla, CA, USA) and MAL (polyclonal, 1:750 with heat retrieval; Stressgen, Victoria, BC, USA), along with one 24-month old WT and one 21-month-old male abcd1 KO.…”

Section: Morphologic Analysesmentioning

confidence: 99%

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The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage

Barron-Casella

Deering

et al. 2007

Laboratory Investigation

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X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that primarily affects the adrenal cortex, as well as myelin and axons of the central nervous system. Marked phenotypic heterogeneity does not correlate with disease-causing mutations in ABCD1, which encodes a peroxisomal membrane protein that is a member of the ABC transmembrane transporter proteins. The precise physiological functions of ABCD1 and ABCD2, a closely related peroxisomal membrane half-transporter, are unknown. The abcd1 knockout mouse does not develop the inflammatory demyelination so typical and devastating in adreno-leukodystrophy, but it does display the same lamellae and lipid profiles in adrenocortical cells under the electron microscope as the human patients. The adrenocortical cells in the mouse also exhibit immunohistochemical evidence of oxidative stress at 12 weeks but no evidence of oxidative damage. To better understand the pathogenesis of this complex disease, we evaluate the adrenal lesion of the abcd1 knockout mouse as a function of normal aging, dietary or therapeutic manipulations, and abcd genotype. The loss of abcd2 causes oxidative stress in the adrenal at 12 weeks, as judged by increased immunoreactivity for the mitochondrial manganese superoxide dismutase, in both the inner cortex and medulla. The loss of abcd2 (n ¼ 20), but not abcd1 (n ¼ 27), results in the spontaneous and premature deposition of ceroid, a known end-product of oxidative damage, predominantly in adrenal medullary cells. These data indicate that the loss of abcd2 results in greater oxidative stress in murine adrenal cells than the loss of abcd1, providing a clue to its cellular function. We also find that the adrenocortical lesion of the abcd1 knockout mouse does not produce functional impairment at ten to nineteen months or overt hypocortisolism at any age, nor does it progress histologically; these and other data align this mouse model closer to human female heterozygotes than to male ALD or AMN hemizygotes.

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confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Morphologic Analysesmentioning

confidence: 99%

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The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage

Barron-Casella

Deering

et al. 2007

Laboratory Investigation

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“…In the past, bile duct-ligated rats showed reduced activities of complex I, II, and III of the electron transport chain, 45 and lipophilic bile acids such as chenodeoxycholate and lithocholate were shown to have an inhibitory effect on complex I and III. 46 Interestingly, mitochondrial anomalies were also reported in adrenocortical cells of a mouse model for X-linked adrenoleukodystrophy, 47 implying the involvement of very long chain fatty acids in the mitochondrial alterations. This is, however, an unlikely mechanism in the L-Pex5 knockout mice, because C26:0 levels were unaltered in liver phospholipids.…”

Section: Discussionmentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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Peroxisome deficiency in men causes severe pathology in several organs, particularly in the brain and liver, but it is still unknown how metabolic abnormalities trigger these defects. In the present study, a mouse model with hepatocyte-selective elimination of peroxisomes was generated by inbreeding Pex5-loxP and albumin-Cre mice to investigate the consequences of peroxisome deletion on the functioning of hepatocytes. Besides the absence of catalase-positive peroxisomes, multiple ultrastructural alterations were noticed, including hepatocyte hypertrophy and hyperplasia, smooth endoplasmic reticulum proliferation, and accumulation of lipid droplets and lysosomes. Most prominent was the abnormal structure of the inner mitochondrial membrane, which bore some similarities with changes observed in Zellweger patients. This was accompanied by severely reduced activities of complex I, III, and V and a collapse of the mitochondrial inner membrane potential. Surprisingly, these abnormalities provoked no significant disturbances of adenosine triphosphate (ATP) levels and redox state of the liver. However, a compensatory increase of glycolysis as an alternative source of ATP and mitochondrial proliferation were observed. No evidence of oxidative damage to proteins or lipids nor elevation of oxidative stress defence mechanisms were found. Altered expression of peroxisome proliferator-activated receptor alpha (PPAR-␣) regulated genes indicated that PPAR-␣ is activated in the peroxisomedeficient cells. In conclusion, the absence of peroxisomes from mouse hepatocytes has an impact on several other subcellular compartments and metabolic pathways but is not detrimental to the function of the liver parenchyma. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). P eroxisomes are indispensable in cellular metabolism, because they harbor enzymes essential for the degradation of very long chain and branched chain fatty acids, for the conversion of cholesterol in bile acids and for the synthesis of ether phospholipids and polyunsaturated fatty acids. They also participate in the catabolism of purines, polyamines, and pipecolic acid. 1 The importance of peroxisomes is stressed by the existence of a group of genetic disorders in which one or more peroxisomal functions are impaired. The most severe is the cerebrohepatorenal syndrome of Zellweger, a peroxisome assembly disorder characterized by the absence of functional peroxisomes due to a disturbance in the peroxisomal protein import machinery. 2 At birth, Zellweger syndrome patients suffer from neurological and eye abnormalities, hypotonia, characteristic craniofacial dysmorphism, and renal cysts. 2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty aci...

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“…Recent investigations (38) could not find alterations of the ␤-oxidation of C24:0 in any of the tissue homogenates from the X-ALD mouse model tested, which prompted the authors to argue against a role of Abcd1 in the degradation of VLCFA. It should be noted that the authors performed C24:0 ␤-oxidation assays using frozen postnuclear supernatants of tissue homogenates or purified peroxisomes from liver (19), which may well account for the different experimental results, especially since the peroxisomal membrane is notoriously fragile upon isolation.…”

Section: Discussionmentioning

confidence: 99%