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

Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL, 08908 L' Hospitalet de Llobregat, Barcelona, Catalonia, Spain. .
Brain (Impact Factor: 9.2). 12/2012; 135(Pt 12):3584-98. DOI: 10.1093/brain/aws292
Source: PubMed


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 ABCD1 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 cannot 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 (Abcd1-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.

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Available from: Cristina Munoz-Pinedo, Feb 13, 2014
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    • "Mitochondrial dysfunction was also reported in cells incubated with exogenous VLCFA (Lopez-Erauskin et al. 2013). Reduced mitochondrial DNA and mitochondrial protein levels were also reported in the white matter of autopsy brain from patients with X-linked adrenoleukodystrophy (Morato et al. 2013, Fourcade et al. 2008, Singh & Pujol 2010, Lopez-Erauskin et al. 2012). In addition to X-ALD, other neurodegenerative diseases are also associated with mitochondrial pathologies (Lin & Beal 2006, Martinez et al. 2010, Pratico 2008, Stack et al. 2008, Zhou et al. 2008, Dai et al. 2014). "
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    ABSTRACT: X-linked Adrenoleukodystrophy (X-ALD), an inherited peroxisomal metabolic neurodegenerative disorder, is caused by mutations/deletions in the ABCD1 gene encoding peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Metabolic dysfunction in X-ALD is characterized by the accumulation of very long chain fatty acids (VLCFAs; ≥ C22:0) in the tissues and plasma of patients. Here, we investigated the mitochondrial status following deletion of ABCD1 in B12 oligodendrocytes and U87 astrocytes. This study provides evidence that silencing of peroxisomal protein ABCD1 produces structural and functional perturbations in mitochondria. Activities of electron transport chain-related enzymes and of citric acid cycle (TCA cycle) were reduced; mitochondrial redox status was dysregulated and the mitochondrial membrane potential was disrupted following ABCD1 silencing. A greater reduction of ATP levels and citrate synthase activities was observed in oligodendrocytes as compared to astrocytes. Further, most of the mitochondrial perturbations induced by ABCD1 silencing were corrected by treating cells with SAHA (suberoylanilide hydroxamic acid), an HDAC inhibitor. These observations indicate a novel relationship between peroxisomes and mitochondria in cellular homeostasis and the importance of intact peroxisomes in relation to mitochondrial integrity and function in the cell types that participate in the pathobiology of X-ALD. These observations suggest SAHA as a potential therapy for X-ALD. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2014 · Journal of Neurochemistry
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    Preview · Article · Nov 2012 · Brain
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    ABSTRACT: Oxidative damage is a pivotal aetiopathogenic factor in X-linked adrenoleukodystrophy. This is a neurometabolic disease characterized by the accumulation of very-long-chain fatty acids owing to the loss of function of the peroxisomal transporter Abcd1. Here, we used the X-linked adrenoleukodystrophy mouse model and patient's fibroblasts to detect malfunctioning of the ubiquitin-proteasome system resulting from the accumulation of oxidatively modified proteins, some involved in bioenergetic metabolism. Furthermore, the immunoproteasome machinery appears upregulated in response to oxidative stress, in the absence of overt inflammation. i-Proteasomes are recruited to mitochondria when fibroblasts are exposed to an excess of very-long-chain fatty acids in response to oxidative stress. Antioxidant treatment regulates proteasome expression, prevents i-proteasome induction and translocation of i-proteasomes to mitochondria. Our findings support a key role of i-proteasomes in quality control in mitochondria during oxidative damage in X-linked adrenoleukodystrophy, and perhaps in other neurodegenerative conditions with similar pathogeneses.
    Full-text · Article · Mar 2013 · Brain
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