Disruption of mitochondrial function in adrenoleukodystrophy



Written on Tuesday 15 July 2014

ALD is an inherited neurodegenerative disease characterized by demyelination in the brain and/or axon injury in the spinal cord, adrenal insufficiency and accumulation of very long chain fatty acids (VLCFAs) in plasma and tissues. ALD is caused by the dysfunction of the ABCD1 gene that encodes a VLCFA transporter in the peroxisome, a component of the cell whose role is to degrade these fatty acids. Thus, the absence of this transporter in mice leads to a late degeneration of axons, the neuron processes, and locomotor problems similar to those seen in cases of adrenomyeloneuropathy in humans. An excess of VLCFAs, notably C26:0, induces oxidative damage leading to axonal degeneration.
In this study, the harmful effect of the C26:0 fatty acid on the mitochondrial function of patients’ skin cells and spinal cord of affected mice is evaluated.
In patients’ cells, the excess of this fatty acid oxidises the DNA of the mitochondria, the energy generator of a cell, and induces the production of free radicals. A marked oxidation of the spinal cord is also observed at a pre-symptomatic stage in the sick mouse.
This study highlights the critical role of the disruption of mitochondrial functions in the neurodegenerative cascade produced in ALD leading to the degeneration of axons. It opens the door to new anti-oxidant treatments targeting mitochondria.

Illness: X-linked adrenoleukodystrophy (ALD)
Experimental model: Patients’ skin cells; sick mice carrying a mutated ABCD1 gene
Study type: Pathophysiopathology
Laboratory: Dr Aurora Pujol, Laboratory of neurometabolic diseases, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
Funding: ELA

Source : J. López-Erauskin, J. Galino, M. Ruiz, J.M. Cuezva, I. Fabregat, D. Cacabelos, J. Boada, J. Martínez, I. Ferrer, R. Pamplona, F. Villarroya, M. Portero-Otín, S. Fourcade, A. Pujol. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum. Mol. Genet. 2013, 22(16):3296-305.

Scientific information provided in collaboration with the INIST-CNRS Institute, (Institute for Scientific and Technical Information)

p-cnrsfilaire_quadri