000			02628na a2200337 4500
999			_c1346 _d1346
003			PC1346
005			20210625062756.0
008			130622s2013 xxx||||| |||| 00| 0 eng d
040			_cH12O
041			_aeng
100			_aCuezva, J.M. _91891 _eInstituto de Investigación i+12
245	0	0	_aImpaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. _h[artículo]
260			_bHuman Molecular Genetics, _c2013
300			_a22(16):3296-305.
500			_aFormato Vancouver: López-Erauskin J, Galino J, Ruiz M, Cuezva JM, Fabregat I, Cacabelos D et al. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum Mol Genet. 2013 Aug 15;22(16):3296-305.
501			_aPMID: 23604518
504			_aContiene 60 referencias
520			_aX-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous system characterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA. In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. We have formerly shown that an excess of the VLCFA C26:0 induces oxidative damage, which underlies the axonal degeneration exhibited by the Abcd1 mice. In the present study, we sought to investigate the noxious effects of C26:0 on mitochondria function. Our data indicate that in X-ALD patients fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) triggering mitochondrial ROS production from electron transport chain complexes. This correlates with impaired complex V phosphorylative activity, as visualized by high-resolution respirometry on spinal cord slices of Abcd1 mice. Further, we identified a marked oxidation of key OXPHOS system subunits in Abcd1 mouse spinal cords at presymptomatic stages. Altogether, our results illustrate some of the mechanistic intricacies by which the excess of a fatty acid targeted to peroxisomes activates a deleterious process of oxidative damage to mitochondria, leading to a multifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALD.
710			_9625 _aInstituto de Investigación imas12
856			_uhttp://pc-h12o-es.m-hdoct.a17.csinet.es/pdf/pc/1/pc1346.pdf _ySolicitar documento
942			_n0 _2ddc _cART