Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy.

[adrenomyeloneuropathy]

X-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 ABCD 1 gene , which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA . In the mouse , Abcd 1 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 C 2 6 :0 induces oxidative damage , which underlies the axonal degeneration exhibited by the Abcd 1 (-) mice . In the present study , we sought to investigate the noxious effects of C 2 6 :0 on mitochondria function . Our data indicate that in X-ALD patients ' fibroblasts , excess of C 2 6 :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 Abcd 1 (-) mice . Further , we identified a marked oxidation of key OXPHOS system subunits in Abcd 1 (-) 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 .

Diseases
Validation

Diseases presenting "high-resolution respirometry on spinal cord" symptom

adrenomyeloneuropathy

x-linked adrenoleukodystrophy

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