期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 445, 期 1, 页码 126-131出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2014.01.126
关键词
AMPK alpha 1; X-ALD; Ubiquitin; Inflammation; OCR; ECAR
资金
- Proposal Development Grant of Henry Ford Health System [A30916]
X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very-long-chain (VLC) fatty acids, which induces inflammatory disease and alterations in cellular redox, both of which are reported to play a role in the pathogenesis of the severe form of the disease (childhood cerebral ALD). While the mutation defect in ABCD1 gene is common to all forms of X-ALD it fails to account for the spectrum of phenotypic variability seen in X-ALD patients, strongly suggesting a role for as yet unidentified modifier gene(s). Here we report, for the first time, loss of AMP-activated protein kinase alpha1 (AMPK alpha 1) in patient-derived fibroblasts and lymphocytes of the severe cerebral form of X-ALD (AID), and not in the milder adrenomyeloneuropathy (AMN) form. Decrease in AMPK was observed at both protein and mRNA levels. AMPK loss in ALD patient-derived fibroblasts was associated with increased ubiquitination. Using the Seahorse Bioscience XF(e)96 Flux Analyzer for measuring the mitochondrial oxygen consumption and extracellular acidification rate we show that ALD patient-derived fibroblasts have a significantly lower metabolic state than AMN fibroblasts. Unstimulated ALD patient-derived lymphocytes had significantly higher proinflammatory gene expression. Selective AMPK loss represents a novel physiopathogenic factor in X-ALD disease mechanism. Strategies aimed at upregulating/recovering AMPK levels might have beneficial therapeutic effects in X-ALD. (C) 2014 Elsevier Inc. All rights reserved.
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