Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy.

[adrenomyeloneuropathy]

A common process associated with oxidative stress and severe mitochondrial impairment is the opening of the mitochondrial permeability transition pore , as described in many neurodegenerative diseases . Thus , inhibition of mitochondrial permeability transition pore opening represents a potential target for inhibiting mitochondrial -driven cell death . Among the mitochondrial permeability transition pore components , cyclophilin D is the most studied and has been found increased under pathological conditions . Here , we have used in vitro and in vivo models of X-linked adrenoleukodystrophy to investigate the relationship between the mitochondrial permeability transition pore opening and redox homeostasis . X-linked adrenoleukodystrophy is a neurodegenerative condition caused by loss of function of the peroxisomal ABCD 1 transporter , in which oxidative stress plays a pivotal role . In this study , we provide evidence of impaired mitochondrial metabolism in a peroxisomal disease , as fibroblasts in patients with X-linked adrenoleukodystrophy can not survive when forced to rely on mitochondrial energy production , i .e . on incubation in galactose . Oxidative stress induced under galactose conditions leads to mitochondrial damage in the form of mitochondrial inner membrane potential dissipation , ATP drop and necrotic cell death , together with increased levels of oxidative modifications in cyclophilin D protein . Moreover , we show increased expression levels of cyclophilin D in the affected zones of brains in patients with adrenomyeloneuropathy , in spinal cord of a mouse model of X-linked adrenoleukodystrophy (Abcd 1 -null mice ) and in fibroblasts from patients with X-linked adrenoleukodystrophy . Notably , treatment with antioxidants rescues mitochondrial damage markers in fibroblasts from patients with X-linked adrenoleukodystrophy , including cyclophilin D oxidative modifications , and reverses cyclophilin D induction in vitro and in vivo . These findings provide mechanistic insight into the beneficial effects of antioxidants in neurodegenerative and non-neurodegenerative cyclophilin D-dependent disorders .

Diseases
Validation

Diseases presenting "mitochondrial permeability transition pore opening" symptom

adrenomyeloneuropathy

x-linked adrenoleukodystrophy

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